Journal articles: 'Brain microvascular endothelium'

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Avsenik, Jernej, Sotirios Bisdas, and Katarina Surlan Popovic. "Blood-brain barrier permeability imaging using perfusion computed tomography." Radiology and Oncology 49, no. 2 (June 1, 2015): 107–14. http://dx.doi.org/10.2478/raon-2014-0029.

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Abstract Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases. Conclusions. Blood-brain barrier permeability can be evaluated in vivo by perfusion computed tomography - an efficient diagnostic method that involves the sequential acquisition of tomographic images during the intravenous administration of iodinated contrast material. The major clinical applications of perfusion computed tomography are in acute stroke and in brain tumor imaging.

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Rochfort, Keith D., Laura E. Collins, Alisha McLoughlin, and Philip M. Cummins. "Shear-Dependent Attenuation of Cellular ROS Levels can Suppress Proinflammatory Cytokine Injury to Human Brain Microvascular Endothelial Barrier Properties." Journal of Cerebral Blood Flow & Metabolism 35, no. 10 (May 20, 2015): 1648–56. http://dx.doi.org/10.1038/jcbfm.2015.102.

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The regulatory interplay between laminar shear stress and proinflammatory cytokines during homeostatic maintenance of the brain microvascular endothelium is largely undefined. We hypothesized that laminar shear could counteract the injurious actions of proinflammatory cytokines on human brain microvascular endothelial cell (HBMvEC) barrier properties, in-part through suppression of cellular redox signaling. For these investigations, HBMvECs were exposed to either shear stress (8 dynes/cm2, 24 hours) or cytokines (tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6), 0 to 100 ng/mL, 6 or 18 hours). Human brain microvascular endothelial cell ‘preshearing’ ± cytokine exposure was also performed. Either cytokine dose–dependently decreased expression and increased phosphorylation (pTyr/pThr) of interendothelial occludin, claudin-5, and vascular endothelial-cadherin; observations directly correlating to endothelial barrier reduction, and in precise contrast to effects seen with shear. We further observed that, relative to unsheared cells, HBMvECs presheared for 24 hours exhibited significantly reduced reactive oxygen species production and barrier permeabilization in response to either TNF-α or IL-6 treatment. Shear also downregulated NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) activation in HBMvECs, as manifested in the reduced expression and coassociation of gp91phox and p47phox. These findings lead us to conclude that physiologic shear can protect the brain microvascular endothelium from injurious cytokine effects on interendothelial junctions and barrier function by regulating the cellular redox state in-part through NADPH oxidase inhibition.

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Iovino, Federico, Grietje Molema, and Jetta J. E. Bijlsma. "Platelet Endothelial Cell Adhesion Molecule-1, a Putative Receptor for the Adhesion of Streptococcus pneumoniae to the Vascular Endothelium of the Blood-Brain Barrier." Infection and Immunity 82, no. 9 (June 9, 2014): 3555–66. http://dx.doi.org/10.1128/iai.00046-14.

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ABSTRACTThe Gram-positive bacteriumStreptococcus pneumoniaeis the main causative agent of bacterial meningitis.S. pneumoniaeis thought to invade the central nervous system via the bloodstream by crossing the vascular endothelium of the blood-brain barrier. The exact mechanism by which pneumococci cross endothelial cell barriers before meningitis develops is unknown. Here, we investigated the role of PECAM-1/CD31, one of the major endothelial cell adhesion molecules, inS. pneumoniaeadhesion to vascular endothelium of the blood-brain barrier. Mice were intravenously infected with pneumococci and sacrificed at various time points to represent stages preceding meningitis. Immunofluorescent analysis of brain tissue of infected mice showed that pneumococci colocalized with PECAM-1. In human brain microvascular endothelial cells (HBMEC) incubated withS. pneumoniae, we observed a clear colocalization between PECAM-1 and pneumococci. Blocking of PECAM-1 reduced the adhesion ofS. pneumoniaeto endothelial cellsin vitro, implying that PECAM-1 is involved in pneumococcal adhesion to the cells. Furthermore, using endothelial cell protein lysates, we demonstrated thatS. pneumoniaephysically binds to PECAM-1. Moreover, bothin vitroandin vivoPECAM-1 colocalizes with theS. pneumoniaeadhesion receptor pIgR. Lastly, immunoprecipitation experiments revealed that PECAM-1 can physically interact with pIgR. In summary, we show for the first time that blood-borneS. pneumoniaecolocalizes with PECAM-1 expressed by brain microvascular endothelium and that, in addition, they colocalize with pIgR. We hypothesize that this interaction plays a role in pneumococcal binding to the blood-brain barrier vasculature prior to invasion into the brain.

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Satoh, Kei, Hidemi Yoshida, Tada-Atsu Imalzumi, Masayuki Koyama, and Shigeru Takamatsu. "Production of Platelet-Activating Factor by Porcine Brain Microvascular Endothelial Cells in Culture." Thrombosis and Haemostasis 74, no. 05 (1995): 1335–39. http://dx.doi.org/10.1055/s-0038-1649936.

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SummaryEndothelial cells produce platelet-activating factor (PAF), which is the key process in the interactions between the vascular wall and blood cells. To examine the production of PAF in brain microvasculature we have cultured brain endothelial cells and performed a comparative study with aortic endothelial cells. Fresh porcine brain was homogenized, and microvascular endothelial cells were separated by enzyme digestion. The cells were cultured in medium containing epidermal growth factor and bovine brain extract. Endothelial cells from the aorta of the same animal were cultured in a similar manner. Production of PAF was assessed by ǀ3Hǀacetate incorporation into phospholipids or by radioimmunoassay. Prostacyclin was measured by radioimmunoassay of 6-ketoprostaglandin F1α. The cells produced 1760 ± 403 and 2892 ± 347 dpm/106 cells (n = 4) of PAF when stimulated with brady- kinin and calcium ionophore A23187, each at 1 μM, respectively. Aortic endothelial cells produced 3911 ± 2006 and 8052 ± 2270 dpm/106 cells (n = 4), respectively, and these values were significantly higher than those in brain endothelial cells (p<0.01, U-test). Prostacyclin production was also higher in aortic cells as compared to brain microvascular endothelial cells. In aortic endothelial cells both Ca ionophore A23187 and bradykinin significantly stimulated PMN adherence whereas in brain microvascular cells only Ca ionophore enhanced the adherence. Brain microvascular endothelial cells produce smaller amount of PAF and prostacyclin as compared to aortic endothelial cells, and this fact may imply that the functional integrity of the brain microvascular endothelium is maintained at a low level.

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Janigro, D., G. A. West, E. L. Gordon, and H. R. Winn. "ATP-sensitive K+ channels in rat aorta and brain microvascular endothelial cells." American Journal of Physiology-Cell Physiology 265, no. 3 (September 1, 1993): C812—C821. http://dx.doi.org/10.1152/ajpcell.1993.265.3.c812.

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The endothelium plays an important role in the modulation of vascular tone and blood cell activation. Extensive work has demonstrated that the release of endothelium-derived relaxing factor (EDRF) from the endothelium is evoked by a number of physical and chemical stimuli requiring Ca2+. Because endothelial cells do not express voltage-dependent Ca2+ channels, Ca2+ influxes following receptor activation may be facilitated by cell hyperpolarizations mediated by the activation of K+ conductances. There has been recent interest in the role of ATP-sensitive K+ channels (KATP) suggesting that KATP may play a role in the regulation of blood flow. We have investigated the electrophysiological properties of an ATP-sensitive K+ conductance in whole cell and membrane patches from rat aorta and brain microvascular endothelial cells. Whole cell as well as single-channel currents were increased by either intracellular dialysis of ATP or application of glucose-free/NaCN (2 mM) solutions. Both currents were reversibly blocked by glibenclamide (1-100 microM). The KATP channel opener pinacidil (30 microM) caused activation of an outward current in the presence of physiological intracellular ATP concentrations. In inside-out patches, 10 microM-1 mM ATP invariably caused a dramatic decrease in channel activity. We conclude that both rat aorta and brain microvascular endothelial cells express KATP channels. KATP may play a role in the regulation of endothelial cell resting potential during impaired energy supply and therefore modulate EDRF release and thus cerebral blood flow.

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Garcia-Polite, Fernando, Jordi Martorell, Paula Del Rey-Puech, Pedro Melgar-Lesmes, Caroline C. O’Brien, Jaume Roquer, Angel Ois, Alessandro Principe, Elazer R. Edelman, and Mercedes Balcells. "Pulsatility and high shear stress deteriorate barrier phenotype in brain microvascular endothelium." Journal of Cerebral Blood Flow & Metabolism 37, no. 7 (October 4, 2016): 2614–25. http://dx.doi.org/10.1177/0271678x16672482.

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Microvascular endothelial cells at the blood–brain barrier exhibit a protective phenotype, which is highly induced by biochemical and biomechanical stimuli. Amongst them, shear stress enhances junctional tightness and limits transport at capillary-like levels. Abnormal flow patterns can reduce functional features of macrovascular endothelium. We now examine if this is true in brain microvascular endothelial cells. We suggest in this paper a complex response of endothelial cells to aberrant forces under different flow domains. Human brain microvascular endothelial cells were exposed to physiological or abnormal flow patterns. Physiologic shear (10–20 dyn/cm2) upregulates expression of tight junction markers Zona Occludens 1 (1.7-fold) and Claudin-5 (more than 2-fold). High shear stress (40 dyn/cm2) and/or pulsatility decreased their expression to basal levels and altered junctional morphology. We exposed cells to pathological shear stress patterns followed by capillary-like conditions. Results showed reversible recovery on the expression of tight junction markers. Flow protection of barrier phenotype commensurate with junctional signaling pathways decrease (Src, 0.25-fold, ERK, 0.77-fold) when compared to static conditions. This decrease was lost under high shear and pulsatile flow. In conclusion, abnormal shear stress inherent to systemic vascular disease leads to barrier impairment, which could be reverted by hemodynamic interventions.

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Sahagun, G., S. A. Moore, and M. N. Hart. "Permeability of neutral vs. anionic dextrans in cultured brain microvascular endothelium." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 1 (July 1, 1990): H162—H166. http://dx.doi.org/10.1152/ajpheart.1990.259.1.h162.

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The luminal surface of vascular endothelium contains glycocalyx residues that establish an overall negative charge. Recent evidence has suggested that local endothelial surface charge properties may account for the permeability properties of various macromolecules. It has also been suggested that altered membrane charge on the luminal side may play a role in thrombogenesis and atherogenesis. The relationship of macromolecule charge to endothelial cell permeability was examined in vitro using mouse brain microvessel endothelial cells grown to confluence on a nitrocellulose filter separating a double-chamber system. Endothelial permeability to 4K and 10K fluorescein-labeled neutral dextrans was compared with the permeability to 4K and 10K fluorescein-labeled anionic dextrans (sulfated). After 1 h, there was significantly greater permeability of neutral fluorescein-labeled dextran than of anionic fluorescein-labeled dextran in each particle size. In addition, there was significantly greater permeability of 4K than 10K fluorescein-labeled dextrans of either charge. The findings indicate that charge in addition to size plays an important role in the movement of macromolecules across cultured microvascular endothelial cells.

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Barabutis, Nektarios. "Insights on supporting the aging brain microvascular endothelium." Aging Brain 1 (2021): 100009. http://dx.doi.org/10.1016/j.nbas.2021.100009.

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Chen, Ye, Richard M. McCarron, Joliet Bembry, Christl Ruetzler, Nabil Azzam, Fred A. Lenz, and Maria Spatz. "Nitric Oxide Modulates Endothelin 1-Induced Ca2+ Mobilization and Cytoskeletal F-Actin Filaments in Human Cerebromicrovascular Endothelial Cells." Journal of Cerebral Blood Flow & Metabolism 19, no. 2 (February 1999): 133–38. http://dx.doi.org/10.1097/00004647-199902000-00003.

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A functional interrelation between nitric oxide (NO), the endothelial-derived vasodilating factor, and endothelin 1 (ET-1), the potent vasoconstrictive peptide, was investigated in microvascular endothelium of human brain. Nor-1 dose-dependently decreased the ET-1–stimulated mobilization of Ca2+. This response was mimicked with cGMP and abrogated by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase G. These findings indicate that NO and ET-1 interactions involved in modulation of intracellular Ca2+ are mediated by cGMP/protein kinase G. In addition, Nor-1–mediated effects were associated with rearrangements of cytoskeleton F-actin filaments. The results suggest mechanisms by which NO–ET-1 interactions may contribute to regulation of microvascular function.

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Kaiser, Mathias, Malgorzata Burek, Stefan Britz, Frauke Lankamp, Steffi Ketelhut, Björn Kemper, Carola Förster, Christian Gorzelanny, and Francisco Goycoolea. "The Influence of Capsaicin on the Integrity of Microvascular Endothelial Cell Monolayers." International Journal of Molecular Sciences 20, no. 1 (December 30, 2018): 122. http://dx.doi.org/10.3390/ijms20010122.

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Microvascular endothelial cells are an essential part of many biological barriers, such as the blood–brain barrier (BBB) and the endothelium of the arteries and veins. A reversible opening strategy to increase the permeability of drugs across the BBB could lead to improved therapies due to enhanced drug bioavailability. Vanilloids, such as capsaicin, are known to reversibly open tight junctions of epithelial and endothelial cells. In this study, we used several in vitro assays with the murine endothelial capillary brain cells (line cEND) as a BBB model to characterize the interaction between capsaicin and endothelial tight junctions.

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Janigro, D., T. S. Nguyen, E. L. Gordon, and H. R. Winn. "Physiological properties of ATP-activated cation channels in rat brain microvascular endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 4 (April 1, 1996): H1423—H1434. http://dx.doi.org/10.1152/ajpheart.1996.270.4.h1423.

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Endothelial cells mediate the actions of a variety of vasoactive substances, including ATP. ATP vasodilatatory actions have been shown to depend on a calcium-dependent release of endothelium-derived relaxing factor(s) (EDRF). ATP induced a vasodilatation of pial penetrating microvessels when applied intraluminally; these relaxations were mediated by the endothelium and followed release of nitric oxide (NO), since they were sensitive to blockade of NO-synthesizing enzymes by NG-nitro-L-arginine (1 mM) and NG-mono-methyl-L-arginine (0.1 mM). We have also investigated the electrophysiological actions of extracellular ATP on rat brain microvascular (RBMEC) and bovine aortic endothelial cells (BAEC) using the patch-clamp technique. While BAEC were hyperpolarized by ATP (10 microM), ATP caused the activation of a depolarizing nonselective cation current in brain endothelial cells. NO production measurements by [3H]citrulline assay and by direct amperometric determination also revealed that after exposure to 1-100 microM ATP, RBMEC released NO. NO release from RBMEC was abolished by removal of external calcium. We conclude that, in the brain, ATP exerts its vasoactive roles by altering the electrophysiological properties of endothelial cells by acting on receptor-operated ion channels, thus providing a mechanism for calcium entry and subsequent release of EDRF.

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Shusta, Eric V., Ruben J. Boado, Gary W. Mathern, and William M. Pardridge. "Vascular Genomics of the Human Brain." Journal of Cerebral Blood Flow & Metabolism 22, no. 3 (March 2002): 245–52. http://dx.doi.org/10.1097/00004647-200203000-00001.

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The microvasculature of the human brain plays an important role in the development and maintenance of the central nervous system and in the pathogenesis of brain diseases, and is the site of differential gene expression within the brain. However, human brain microvascular-specific genes may not be detected in whole-brain gene microarray because the volume of the brain microvascular endothelium is relatively small (0.1%) compared with the whole brain. Therefore, the differential gene expression within the human brain microvasculature was evaluated using suppression subtractive hybridization with RNA isolated from human brain microvessels. Gene identification was restricted to the first 71 clones that were differentially expressed at the brain microvasculature. Twenty of these were genes encoding proteins with known function that were involved in angiogenesis, neurogenesis, molecular transport, and maintenance of endothelial tight junctions or the cytoskeleton. Eighteen genes coding for proteins of an unknown function were identified, including five genes containing satellite DNA sequences. The results provide the initial outline of the genomics of the human brain microvasculature, and have implications for the identification of both targets for brain-specific drug transport and changes in microvascular gene expression in brain diseases.

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Hsu, P., M. Shibata, and C. W. Leffler. "Prostanoid synthesis in response to high CO2 in newborn pig brain microvascular endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 5 (May 1, 1993): H1485—H1492. http://dx.doi.org/10.1152/ajpheart.1993.264.5.h1485.

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Hypercapnia-induced cerebral vasodilation involves prostanoids in newborn pigs. However, the source of prostanoids has not been determined. The current study was designed to address the hypothesis that piglet cerebral microvascular endothelial cells increase their synthesis of prostanoids in response to high CO2. Microvascular endothelial cells, smooth muscle cells, and glia were isolated and grown in primary culture. They were identified morphologically and by indirect immunofluorescence staining. Cerebral microvascular endothelial cell cultures from newborn pigs produced equal amounts of 6-ketoprostaglandin (PG) F1 alpha (stable hydrolysis product of PGI2), PGE2 and a small amount of PGF2 alpha under basal conditions. Administration of calcium ionophore A23187 to the endothelial cells increased release of all three prostanoids in a dose- and time-dependent manner. Exposure of piglet cerebral microvascular endothelial cells to higher than normal CO2 increased the production of 6-keto-PGF1 alpha and PGE2 but not of PGF2 alpha. The enhanced prostanoid biosynthesis was concentration dependent, peaking at 14% CO2, and was detected during the first 10 min exposure to 14% CO2. Hypercapnia-induced increased synthesis of prostanoids was blocked dose dependently by the simultaneous addition of PGH synthase inhibitor indomethacin. High CO2 did not increase prostanoid production by cerebral microvascular smooth muscle cells or glia, although A23187 enhanced prostanoid formation by both cell types. These data show that high CO2 stimulates prostanoid synthesis by newborn pig cerebral microvascular endothelial cells, which is consistent with an involvement of cerebral vascular endothelium in hypercapnia-induced vasodilation.

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Lecointre, Maryline, Michelle Hauchecorne, Armelle Chaussivert, Stéphane Marret, Philippe Leroux, Sylvie Jegou, Isabelle Leroux-Nicollet, Bruno J. Gonzalez, and Vincent J. Henry. "The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells." Journal of Cerebral Blood Flow & Metabolism 34, no. 5 (February 12, 2014): 764–67. http://dx.doi.org/10.1038/jcbfm.2014.30.

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Glutamate transporters (excitatory amino-acid transporters (EAATs)) are essential for brain homeostasis. While previous studies indicate that the vascular endothelium contributes to glutamate efflux in the adult brain, little information is available regarding glutamate uptake in the immature brain. The present study shows a differential expression pattern of EAATs between cortical microvessels in adults and newborns. In addition, adult cortical endothelial cells take up glutamate more efficiently than neonatal cells. Our findings indicate age-specific changes in extracellular glutamate regulation by brain endothelial cells, suggesting differences in the efficiency of glutamate efflux during an excitotoxic process that, in turn, may contribute to age-specific brain vulnerability.

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Nottet, H. S., Y. Persidsky, V. G. Sasseville, A. N. Nukuna, P. Bock, Q. H. Zhai, L. R. Sharer, et al. "Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain." Journal of Immunology 156, no. 3 (February 1, 1996): 1284–95. http://dx.doi.org/10.4049/jimmunol.156.3.1284.

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Abstract HIV-1 penetration of the brain is a pivotal event in the neuropathogenesis of AIDS-associated dementia. The establishment of productive viral replication or up-regulation of adhesion molecule expression on brain microvascular endothelial cells (BMVEC) could permit entry of HIV into the central nervous system. To investigate the contribution of both, we inoculated primary human BMVEC with high titer macrophage-tropic HIV-1 or cocultured them with virus-infected monocytes. In both instances, BMVEC failed to demonstrate productive viral replication. Cell to cell contact between monocytes and microvascular endothelium resulted in E-selectin expression on BMVEC. BMVEC. cocultured with LPS-activated HIV-infected monocytes expressed even higher levels of E-selectin and vascular cell adhesion molecule-1 (VCAM-1). Transwell assays supported a role of soluble factors, from virus-infected monocytes, for the induction of adhesion molecules on BMVEC. To verify the in vivo relevance of these findings, levels of adhesion molecules were compared with those of proinflammatory cytokines and HIV-1 gene products in brain tissue of AIDS patients with or without encephalitis and HIV-seronegative controls. E-Selectin, and to a lesser degree VCAM-1, paralleled the levels of HIV-1 gene products and proinflammatory cytokines in brain tissue of subjects with encephalitis. Most importantly, an association between macrophage infiltration and increased endothelial cell adhesion molecules was observed in encephalitic brains. Monocyte binding to encephalitic brain tissue was blocked with Abs to VCAM-1 and E-selectin. These data, taken together, suggest that HIV entry into brain is, in part, a consequence of the ability of virus-infected and immune-activated monocytes to induce adhesion molecules on brain endothelium.

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Engelhardt, Britta. "β1-Integrin/Matrix Interactions Support Blood–Brain Barrier Integrity." Journal of Cerebral Blood Flow & Metabolism 31, no. 10 (July 20, 2011): 1969–71. http://dx.doi.org/10.1038/jcbfm.2011.98.

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Brain microvascular endothelium forms an active permeability barrier, the blood–brain barrier (BBB). In neurologic disorders, barrier properties of the BBB are often lost indicating their dependance on molecular cues of the brain microenvironment. In this issue, Osada et al demonstrate that the endothelial extracellular matrix (ECM) provides one of these cues. Their study shows that β1-integrin-mediated adhesion of brain endothelial cells to the surrounding ECM is critical for stabilizing claudin-5 in BBB tight junctions (TJs) and BBB integrity. These observations point to a novel intracellular signaling pathway from β1-integrin/ECM endothelial adhesions to BBB TJs contributing to BBB integrity.

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Wu, Limin, Mohammad R. Islam, Janice Lee, Hajime Takase, Shuzhen Guo, Allison M. Andrews, Tetyana P. Buzhdygan, et al. "ErbB3 is a critical regulator of cytoskeletal dynamics in brain microvascular endothelial cells: Implications for vascular remodeling and blood brain barrier modulation." Journal of Cerebral Blood Flow & Metabolism 41, no. 9 (February 14, 2021): 2242–55. http://dx.doi.org/10.1177/0271678x20984976.

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Neuregulin (NRG)1 - ErbB receptor signaling has been shown to play an important role in the biological function of peripheral microvascular endothelial cells. However, little is known about how NRG1/ErbB signaling impacts brain endothelial function and blood-brain barrier (BBB) properties. NRG1/ErbB pathways are affected by brain injury; when brain trauma was induced in mice in a controlled cortical impact model, endothelial ErbB3 gene expression was reduced to a greater extent than that of other NRG1 receptors. This finding suggests that ErbB3-mediated processes may be significantly compromised after injury, and that an understanding of ErbB3 function would be important in the of study of endothelial biology in the healthy and injured brain. Towards this goal, cultured brain microvascular endothelial cells were transfected with siRNA to ErbB3, resulting in alterations in F-actin organization and microtubule assembly, cell morphology, migration and angiogenic processes. Importantly, a significant increase in barrier permeability was observed when ErbB3 was downregulated, suggesting ErbB3 involvement in BBB regulation. Overall, these results indicate that neuregulin-1/ErbB3 signaling is intricately connected with the cytoskeletal processes of the brain endothelium and contributes to morphological and angiogenic changes as well as to BBB integrity.

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Schnitzer, J. E. "gp60 is an albumin-binding glycoprotein expressed by continuous endothelium involved in albumin transcytosis." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 1 (January 1, 1992): H246—H254. http://dx.doi.org/10.1152/ajpheart.1992.262.1.h246.

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Albumin reduces capillary permeability and acts as a carrier for various small molecules. Recently, we identified a 60-kDa sialoglycoprotein (gp60) on the surface of cultured rat microvascular endothelial cells (MEC) that binds albumin and antiglycophorin serum (alpha-gp). We verified that alpha-gp recognizes the albumin-binding gp60 by affinity, purifying proteins from MEC extracts using immobilized albumin. gp60 was immunoblotted with alpha-gp only when the MEC extract was reacted with albumin and not in controls. We immunoprecipitated gp60 from biosynthetically radiolabeled MEC lysates and from extracts containing endothelial surface proteins of isolated rat hearts that were radioiodinated in situ. gp60 was immunoblotted selectively in rat tissue microvascular beds lined with continuous endothelium (heart, lung, diaphragm, fat, skeletal muscle, mesentery, and duodenal muscularis but not cortical brain) and not those exclusively lined with fenestrated or sinusoidal endothelium (adrenal, pancreas, liver, and small intestinal mucosa). MEC isolated from rat heart, lung, and epididymal fat pad expressed gp60 and bound albumin, whereas various nonendothelial cells and brain-derived MEC did not. gp60 is an albumin-binding glycoprotein expressed specifically on the surface of continuous endothelium that binds albumin apparently not only to initiate its transcytosis via plasmalemmal vesicles but also to increase capillary permselectivity.

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Staunton, Michael, Cathy Drexler, Michael G. Dulitz, Dale C. Ekbom, William T. Schmeling, and Neil E. Farber. "Effects of Hypoxia–Reoxygenation on Microvascular Endothelial Function in the Rat Hippocampal Slice." Anesthesiology 91, no. 5 (November 1, 1999): 1462. http://dx.doi.org/10.1097/00000542-199911000-00040.

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Background Cerebral ischemia and hypoxia may cause injury to both neuronal and vascular tissue. The direct effects of hypoxia on endothelial function in intraparenchymal cerebral arterioles are unknown. Using a modification of the rat brain slice preparation, allowing continuous imaging of these previously inaccessible vessels, microvessel dilation was evaluated before and after a brief hypoxic episode. Methods Rat brain slices were superfused with oxygenated artificial cerebrospinal fluid. Hippocampal arterioles were visualized using computerized videomicroscopy, and their diameters (range, 12-27 microm) were measured using image analysis. After preconstriction with prostaglandin F2alpha and controlled pH and carbon dioxide tension, graded concentrations of either acetylcholine (endothelium-dependent vasodilation) or sodium nitroprusside (endothelium-independent vasodilation) were given before and after a 10-min period of hypoxia. Results Sodium nitroprusside (100 microM) caused similar dilation before and after hypoxia (mean +/- SEM: 9.6 +/- 0.6% vs. 13.0 +/- 0.9%). Acetylcholine (100 microM) caused significantly less dilation (P < 0.05) after hypoxia (mean +/- SEM: 9.3 +/- 1.8% vs. 3.6 +/- 1.2%). The decreased acetylcholine-induced dilation after hypoxia was not reversed by pretreatment with L-arginine (1 mM), the precursor of nitric oxide (mean +/- SEM: 8.8 +/- 1.3% vs. 4.4 +/- 0.7%). Conclusions Even brief periods of hypoxia may cause endothelial dysfunction in intraparenchymal cerebral arterioles. This does not seem to be related to a deficiency of the nitric oxide substrate, L-arginine. Endothelial dysfunction and impaired endothelium-dependent dilation of microvessels may decrease oxygen delivery and increase neuronal injury during cerebral hypoxia-reoxygenation.

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Neglia, Laura, Stefano Fumagalli, Franca Orsini, Adriana Zanetti, Carlo Perego, and Maria-Grazia De Simoni. "Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells." Journal of Cerebral Blood Flow & Metabolism 40, no. 8 (September 7, 2019): 1608–20. http://dx.doi.org/10.1177/0271678x19874509.

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Mannose-binding lectin (MBL), an initiator of the lectin pathway, is detrimental in ischemic stroke. MBL deposition on the ischemic endothelium indicates the beginning of its actions, but downstream mechanisms are not clear yet. We investigated MBL interactions with the ischemic endothelium by exposing human brain microvascular endothelial cells (hBMECs) to protocols of ischemia. Cells were exposed to hypoxia or oxygen–glucose deprivation (OGD), and re-oxygenated with human serum (HS) or recombinant MBL (rhMBL). Hypoxic hBMECs re-oxygenated with HS showed increased complement system activation (C3c deposition, +59%) and MBL deposition (+93%) than normoxic cells. Super-resolution microscopy showed MBL internalization in hypoxic cells and altered cytoskeletal organization, indicating a potential MBL action on the endothelial structure. To isolate MBL effect, hBMECs were re-oxygenated with rhMBL after hypoxia/OGD. In both conditions, MBL reduced viability (hypoxia: −25%, OGD: −34%) compared to conditions without MBL, showing a direct toxic effect. Ischemic cells also showed greater MBL deposition (hypoxia: +143%, OGD: +126%) than normoxic cells. These results were confirmed with primary hBMECs exposed to OGD (increased MBL-induced cell death: +226%, and MBL deposition: +104%). The present findings demonstrate that MBL can exert a direct deleterious effect on ischemic brain endothelial cells in vitro, independently from complement activation.

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Beard, Richard S., Jason J. Reynolds, and Shawn E. Bearden. "Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions." Blood 118, no. 7 (August 18, 2011): 2007–14. http://dx.doi.org/10.1182/blood-2011-02-338269.

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Abstract Hyperhomocysteinemia (HHcy) increases permeability of the blood-brain barrier, but the mechanisms are undetermined. Homocysteine (Hcy) is an agonist of the neuronal N-methyl-D-aspartate receptor (NMDAr). We tested the hypothesis that HHcy disrupts the blood-brain barrier by an NMDAr-dependent mechanism in endothelium. In brain microvascular endothelial cells, there was no change in expression of the adherens junction protein VE-cadherin with Hcy treatment, but there was a significant decrease in the amount of β-catenin at the membrane. Moreover, Hcy caused nuclear translocation of β-catenin and attachment to the promoter for the tight junction protein claudin-5, with concomitant reduction in claudin-5 expression. Using a murine model of HHcy (cbs+/−), treatment for 2 weeks with an NMDAr antagonist (memantine) rescued cerebrovascular expression of claudin-5 and blood-brain barrier permeability to both exogenous sodium fluorescein and endogenous IgG. Memantine had no effect on these parameters in wild-type littermates. The same results were obtained using an in vitro model with brain microvascular endothelial cells. These data provide the first evidence that the NMDAr is required for Hcy-mediated increases in blood-brain barrier permeability. Modulating cerebral microvascular NMDAr activity may present a novel therapeutic target in diseases associated with opening of the blood-brain barrier in HHcy, such as stroke and dementia.

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Lu, Tyler M., Sean Houghton, Tarig Magdeldin, José Gabriel Barcia Durán, Andrew P. Minotti, Amanda Snead, Andrew Sproul, et al. "Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate." Proceedings of the National Academy of Sciences 118, no. 8 (February 4, 2021): e2016950118. http://dx.doi.org/10.1073/pnas.2016950118.

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Cells derived from pluripotent sources in vitro must resemble those found in vivo as closely as possible at both transcriptional and functional levels in order to be a useful tool for studying diseases and developing therapeutics. Recently, differentiation of human pluripotent stem cells (hPSCs) into brain microvascular endothelial cells (ECs) with blood–brain barrier (BBB)-like properties has been reported. These cells have since been used as a robust in vitro BBB model for drug delivery and mechanistic understanding of neurological diseases. However, the precise cellular identity of these induced brain microvascular endothelial cells (iBMECs) has not been well described. Employing a comprehensive transcriptomic metaanalysis of previously published hPSC-derived cells validated by physiological assays, we demonstrate that iBMECs lack functional attributes of ECs since they are deficient in vascular lineage genes while expressing clusters of genes related to the neuroectodermal epithelial lineage (Epi-iBMEC). Overexpression of key endothelial ETS transcription factors (ETV2, ERG, and FLI1) reprograms Epi-iBMECs into authentic endothelial cells that are congruent with bona fide endothelium at both transcriptomic as well as some functional levels. This approach could eventually be used to develop a robust human BBB model in vitro that resembles the human brain EC in vivo for functional studies and drug discovery.

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Bacic, F., S. Uematsu, R. M. McCarron, and M. Spatz. "Secretion of Immunoreactive endothelin-1 by capillary and microvascular endothelium of human brain." Neurochemical Research 17, no. 7 (July 1992): 699–702. http://dx.doi.org/10.1007/bf00968008.

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Chandra, Partha K., Ibolya Rutkai, Hogyoung Kim, Stephen E. Braun, Asim B. Abdel-Mageed, Debasis Mondal, and David W. Busija. "Latent HIV-Exosomes Induce Mitochondrial Hyperfusion Due to Loss of Phosphorylated Dynamin-Related Protein 1 in Brain Endothelium." Molecular Neurobiology 58, no. 6 (February 14, 2021): 2974–89. http://dx.doi.org/10.1007/s12035-021-02319-8.

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AbstractDamage to the cerebral vascular endothelium is a critical initiating event in the development of HIV-1-associated neurocognitive disorders. To study the role of mitochondria in cerebral endothelial dysfunction, we investigated how exosomes, isolated from both cell lines with integrated provirus and HIV-1 infected primary cells (HIV-exosomes), accelerate the dysfunction of primary human brain microvascular endothelial cells (HBMVECs) by inducing mitochondrial hyperfusion, and reducing the expression of phosphorylated endothelial nitric oxide synthase (p-eNOS). The quantitative analysis of the extracellular vesicles (EVs) indicates that the isolated EVs were predominantly exosomes. It was further supported by the detection of exosomal markers, and the absence of large EV-related protein in the isolated EVs. The exosomes were readily taken up by primary HBMVECs. HIV-exosomes induce cellular and mitochondrial superoxide production but reduce mitochondrial membrane potential in HBMVECs. HIV-exosomes increase mitochondrial hyperfusion, possibly due to loss of phosphorylated dynamin-related protein 1 (p-DRP1). HIV-exosomes, containing the HIV-Tat protein, and viral Tat protein reduce the expression of p-DRP1 and p-eNOS, and accelerate brain endothelial dysfunction. Finally, exosomes isolated from HIV-1 infected primary human peripheral blood mononuclear cells (hPBMCs) produce more exosomes than uninfected controls and reduce both p-DRP1 and p-eNOS expressions in primary HBMVECs. Our novel findings reveal the significant role of HIV-exosomes on dysregulation of mitochondrial function, which induces adverse changes in the function of the brain microvascular endothelium.

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Vazquez-Liebanas, Elisa, Khayrun Nahar, Giacomo Bertuzzi, Annika Keller, Christer Betsholtz, and Maarja Andaloussi Mäe. "Adult-induced genetic ablation distinguishes PDGFB roles in blood-brain barrier maintenance and development." Journal of Cerebral Blood Flow & Metabolism 42, no. 2 (October 25, 2021): 264–79. http://dx.doi.org/10.1177/0271678x211056395.

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Platelet-derived growth factor B (PDGFB) released from endothelial cells is indispensable for pericyte recruitment during angiogenesis in embryonic and postnatal organ growth. Constitutive genetic loss-of-function of PDGFB leads to pericyte hypoplasia and the formation of a sparse, dilated and venous-shifted brain microvasculature with dysfunctional blood-brain barrier (BBB) in mice, as well as the formation of microvascular calcification in both mice and humans. Endothelial PDGFB is also expressed in the adult quiescent microvasculature, but here its importance is unknown. We show that deletion of Pdgfb in endothelial cells in 2-months-old mice causes a slowly progressing pericyte loss leading, at 12–18 months of age, to ≈50% decrease in endothelial:pericyte cell ratio, ≈60% decrease in pericyte longitudinal capillary coverage and >70% decrease in pericyte marker expression. Similar to constitutive loss of Pdgfb, this correlates with increased BBB permeability. However, in contrast to the constitutive loss of Pdgfb, adult-induced loss does not lead to vessel dilation, impaired arterio-venous zonation or the formation of microvascular calcifications. We conclude that PDFGB expression in quiescent adult microvascular brain endothelium is critical for the maintenance of pericyte coverage and normal BBB function, but that microvessel dilation, rarefaction, arterio-venous skewing and calcification reflect developmental roles of PDGFB.

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Rom, Slava, Holly Dykstra, Viviana Zuluaga-Ramirez, Nancy L. Reichenbach, and Yuri Persidsky. "miR-98 and let-7g* Protect the Blood-Brain Barrier Under Neuroinflammatory Conditions." Journal of Cerebral Blood Flow & Metabolism 35, no. 12 (July 1, 2015): 1957–65. http://dx.doi.org/10.1038/jcbfm.2015.154.

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Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3β inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3β inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier ‘leakiness’ in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation.

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Watson, Ashley N., Andree-Anne Berthiaume, Anna V. Faino, Konnor P. McDowell, Narayan R. Bhat, David A. Hartmann, and Andy Y. Shih. "Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRβ+/− mice." Journal of Cerebral Blood Flow & Metabolism 40, no. 12 (January 27, 2020): 2387–400. http://dx.doi.org/10.1177/0271678x19900543.

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The receptor tyrosine kinase PDGFRβ is essential for pericyte migration to the endothelium. In mice lacking one allele of PDGFRβ (PDGFRβ+/−), previous reports have described an age-dependent loss of pericytes in the brain, leading to cerebrovascular dysfunction and subsequent neurodegeneration reminiscent of that seen in Alzheimer’s disease and vascular dementia. We examined 12–20-month-old PDGFRβ+/− mice to better understand how pericyte loss affects brain microvascular structure and perfusion in vivo. We observed a mild reduction of cortical pericyte number in PDGFRβ+/− mice (27% fewer cell bodies) compared to controls, but no decrease in pericyte coverage of the endothelium. This mild degree of pericyte loss caused no discernable change in cortical microvascular density, length, basal diameter or reactivity to hypercapnia. Yet, it was associated with an increase in basal blood cell velocity, primarily in pre-capillary arterioles. Taken together, our results suggest that mild pericyte loss can lead to aberrant cerebral blood flow despite a lack of apparent effect on microvascular structure and reactivity.

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Chen, Yizhao, Osamu Tachibana, Mitsuhiro Hasegawa, Ruxiang Xu, Jun-ichiro Hamada, Junkoh Yamashita, Nobuo Hashimoto, and Jun A. Takahashi. "Absence of Tight Junctions between Microvascular Endothelial Cells in Human Cerebellar Hemangioblastomas." Neurosurgery 59, no. 3 (September 1, 2006): 660–70. http://dx.doi.org/10.1227/01.neu.0000223372.18607.d7.

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Abstract OBJECTIVE: Endothelial tight junctions form the main barrier of the blood-brain barrier (BBB). In human hemangioblastomas, cyst formation is a common and important clinical manifestation. Although most researchers consider that the cyst formation in hemangioblastomas may be caused by the breakdown of the BBB, the underlying molecular mechanisms for cyst formation remain unknown. At present, there are few reports about the change of tight junctions in microvessel endothelium of human hemangioblastomas. The purpose of this research is to investigate the change of tight junction and its major molecular components in microvessel endothelium of human hemangioblastomas. METHODS: Twenty-four consecutive patients with cerebellar hemangioblastomas were studied. Tight junctions in the microvessels of hemangioblastomas and the control brain were examined by electron microscopy. Immunohistochemistry and double immunofluorescent microscopy were used to analyze the expression of CLN5 and its relationship with astrocytic endfeet in the control brain and hemangioblastomas. Quantitative real-time reverse-transcriptase polymerase chain reaction and Western blots were used to investigate the expression level of CLN5 in hemangioblastomas. Triple immunofluorescent microscopy was used to analyze the coexpression of vascular endothelial growth factor, vascular endothelial growth factor-R1, and placenta growth factor on microvessels of hemangioblastomas. Clinical and experimental data were correlated and analyzed by the one-way analysis of variance, Kruskal-Wallis test, and Spearman rank correlation test. RESULTS: In the control brain, the paracellular cleft between adjacent endothelial cells is sealed by continuous strands of tight junctions. In cystic hemangioblastomas, a significant paracellular cleft could be found between adjacent endothelial cells. Some endothelial cells were connected with adherens junction and no tight junction was found between them. Compared with the control brain, expression of CLN5 was decreased in cystic hemangioblastomas (P < 0.05). Phosphorylated CLN5 was detected in most hemangioblastomas, but not in the control brain. Microvessels in hemangioblastomas showed a significant absence of astrocytic endfeet. Coexpression of vascular endothelial growth factor, vascular endothelial growth factor-R1, and placenta growth factor was detected in the endothelial cells. The Spearman rank correlation test showed a significant correlation between a greater degree of CLN5 expression and less morphological cystic formation in these patients studied (correlation coefficient = −0.520; P = 0.009). CONCLUSION: The continuity of tight junctions of the BBB is interrupted in human cerebellar hemangioblastomas. Significant absence of astrocytic endfeet and tight junctions can be found in microvessels of hemangioblastomas, which may lead to the breakdown of the BBB in these tumors. These findings suggest that the absence of tight junctions might play a role in cyst formation of hemangioblastomas.

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Uddin, Mohammad A., Mohammad S. Akhter, Khadeja-Tul Kubra, Kathryn E. Whitaker, Summer L. Shipley, Landon M. Smith, and Nektarios Barabutis. "Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress." Brain Disorders 1 (March 2021): 100001. http://dx.doi.org/10.1016/j.dscb.2020.100001.

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Pranda, Marina A., Kelsey M. Gray, Ariana Joy L. DeCastro, Gregory M. Dawson, Jae W. Jung, and Kimberly M. Stroka. "Tumor Cell Mechanosensing During Incorporation into the Brain Microvascular Endothelium." Cellular and Molecular Bioengineering 12, no. 5 (August 28, 2019): 455–80. http://dx.doi.org/10.1007/s12195-019-00591-2.

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Bhattarai, Susmita, Sudha Sharma, Utsab Subedi, Hosne Ara, Alika Shum, Murov Milena, Md Shenuarin Bhuiyan, et al. "The ATX–LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion." International Journal of Molecular Sciences 23, no. 8 (April 8, 2022): 4138. http://dx.doi.org/10.3390/ijms23084138.

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Endothelial permeability is a major complication that must be addressed during stroke treatment. Study of the mechanisms underlying blood–brain barrier (BBB) disruption and management of the hypoxic stress-induced permeability of the endothelium following reperfusion are both urgently needed for stroke management. Lysophosphatidic acid (LPA), a bioactive lipid essential for basic cellular functions, causes unfavorable outcomes during stroke progression. LPA-producing enzyme autotaxin (ATX) is regulated in ischemic stroke. We used an electrical cell-substrate impedance sensor (ECIS) to measure endothelial permeability. Mitochondrial bioenergetics were obtained using a Seahorse analyzer. AR-2 probe fluorescence assay was used to measure ATX activity. LPA increased endothelial permeability and reduced junctional protein expression in mouse brain microvascular endothelial cells (MBMEC). LPA receptor inhibitors Ki16425 and AM095 attenuated the LPA-induced changes in the endothelial permeability and junctional proteins. LPA significantly diminished mitochondrial function in MBMEC. ATX was upregulated (p < 0.05) in brain microvascular endothelial cells under hypoxic reperfusion. ATX activity and permeability were attenuated with the use of an ATX inhibitor in a mouse stroke model. The upregulation of ATX with hypoxic reperfusion leads to LPA production in brain endothelial cells favoring permeability. Inhibition of the ATX–LPA–LPAR axis could be therapeutically targeted in stroke to achieve better outcomes.

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Verbeek, M. M., J. R. Westphal, D. J. Ruiter, and R. M. de Waal. "T lymphocyte adhesion to human brain pericytes is mediated via very late antigen-4/vascular cell adhesion molecule-1 interactions." Journal of Immunology 154, no. 11 (June 1, 1995): 5876–84. http://dx.doi.org/10.4049/jimmunol.154.11.5876.

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Abstract T cell adhesion to the brain microvascular endothelium and subsequent migration into the brain parenchyma is one of the major events in the development of multiple sclerosis (MS). Interactions of the T cell integrin very late antigen-4 (VLA-4) with its receptor, vascular cell adhesion molecule-1 (VCAM-1) have been described to be of crucial importance for the development of MS. We investigated the expression of these adhesion molecules in MS brain tissue by immunohistochemical analysis, and studied their functional involvement in an in vitro T cell adhesion assay. A number of other adhesion molecules were studied for comparison. In cryosections of several MS brains, expression of VCAM-1 was demonstrated not only on the endothelium of vessels surrounding MS plaques, but also in perivascular positions, suggesting expression by pericytes. T cells adhered to both cell types in vitro. Both LFA-1/intercellular adhesion molecule-1 and VLA-4/VCAM-1 interactions were equally involved in the adhesion of T cells to TNF-alpha-stimulated endothelial cells. However, adhesion of T cells to TNF-alpha-stimulated pericytes was clearly dominated by VLA-4/VCAM-1 interactions. These results indicate that pericytes, next to endothelial cells, may play an important role in regulating T cell infiltration into the central nervous system.

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Li, Wei, Carmina Busu, Magdalena L. Circu, and Tak Yee Aw. "Glutathione in Cerebral Microvascular Endothelial Biology and Pathobiology: Implications for Brain Homeostasis." International Journal of Cell Biology 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/434971.

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The integrity of the vascular endothelium of the blood-brain barrier (BBB) is central to cerebrovascular homeostasis. Given the function of the BBB as a physical and metabolic barrier that buffers the systemic environment, oxidative damage to the endothelial monolayer will have significant deleterious impact on the metabolic, immunological, and neurological functions of the brain. Glutathione (GSH) is a ubiquitous major thiol within mammalian cells that plays important roles in antioxidant defense, oxidation-reduction reactions in metabolic pathways, and redox signaling. The existence of distinct GSH pools within the subcellular organelles supports an elegant mode for independent redox regulation of metabolic processes, including those that control cell fate. GSH-dependent homeostatic control of neurovascular function is relatively unexplored. Significantly, GSH regulation of two aspects of endothelial function is paramount to barrier preservation, namely, GSH protection against oxidative endothelial cell injury and GSH control of postdamage cell proliferation in endothelial repair and/or wound healing. This paper highlights our current insights and hypotheses into the role of GSH in cerebral microvascular biology and pathobiology with special focus on endothelial GSH and vascular integrity, oxidative disruption of endothelial barrier function, GSH regulation of endothelial cell proliferation, and the pathological implications of GSH disruption in oxidative stress-associated neurovascular disorders, such as diabetes and stroke.

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Li, Yi, Xiao-Tian Liu, Pei-Lin Zhang, Yu-Chen Li, Meng-Ru Sun, Yi-Tao Wang, Sheng-Peng Wang, et al. "Hydroxysafflor Yellow A Blocks HIF-1α Induction of NOX2 and Protects ZO-1 Protein in Cerebral Microvascular Endothelium." Antioxidants 11, no. 4 (April 7, 2022): 728. http://dx.doi.org/10.3390/antiox11040728.

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Zonula occludens-1 (ZO-1) is a tight junction protein in the cerebrovascular endothelium, responsible for blood–brain barrier function. Hydroxysafflor yellow A (HSYA) is a major ingredient of safflower (Carthamus tinctorius L.) with antioxidative activity. This study investigated whether HSYA protected ZO-1 by targeting ROS-generating NADPH oxidases (NOXs). HSYA administration reduced cerebral vascular leakage with ZO-1 protection in mice after photothrombotic stroke, largely due to suppression of ROS-associated inflammation. In LPS-stimulated brain microvascular endothelial cells, HSYA increased the ratio of NAD+/NADH to restore Sirt1 induction, which bound to Von Hippel–Lindau to promote HIF-1αdegradation. NOX2 was the predominant isoform of NOXs in endothelial cells and HIF-1α transcriptionally upregulated p47phox and Nox2 subunits for the assembly of the NOX2 complex, but the signaling cascades were blocked by HSYA via HIF-1α inactivation. When oxidate stress impaired ZO-1 protein, HSYA attenuated carbonyl modification and prevented ZO-1 protein from 20S proteasomal degradation, eventually protecting endothelial integrity. In microvascular ZO-1 deficient mice, we further confirmed that HSYA protected cerebrovascular integrity and attenuated ischemic injury in a manner that was dependent on ZO-1 protection. HSYA blocked HIF-1α/NOX2 signaling cascades to protect ZO-1 stability, suggestive of a potential therapeutic strategy against ischemic brain injury.

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Greune, Lilo, Björn Kemper, Ulrich Dobrindt, Joyce Geelen, Kwang Kim, M. Alexander Schmidt, Helge Karch, Martina Bielaszewska, and Andreas Bauwens. "Vacuolisation of human microvascular endothelial cells by enterohaemorrhagic Escherichia coli." Thrombosis and Haemostasis 102, no. 12 (2009): 1080–92. http://dx.doi.org/10.1160/th09-07-0499.

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SummaryEnterohaemorrhagic Escherichia coli (EHEC) cause haemolytic uraemic syndrome (HUS),a thrombotic microangiopathy resulting from endothelial injury in the renal glomeruli and other organs. EHEC virulence factors that damage the microvascular endothelium play therefore major roles in the pathogenesis of HUS.We identified an EHEC strain that vacuolates and kills primary human glomerular microvascular endothelial cells (GMVECs) and a human brain microvascular endothelial cell (HBMEC) line. Because the vacuolating effect closely resembles those elicited on other cells by the vacuolating cytotoxin of Helicobacter pylori (VacA), we designated the factor responsible for this effect EHEC vacuolating cytotoxin (EHEC-Vac). EHEC-Vac (a secreted non-serine protease protein) binds to HBMECs rapidly and irreversibly, vacuolates within 30 min after exposure and the effect is maximally apparent at 48 h. Despite the vacuolisation, HBMECs survive for several days before they undergo necrosis. Electron and immunofluorescence microscopy demonstrate that the vacuoles induced by EHEC-Vac originate from lysosomes.Accordingly, they stain with neutral red indicating an acidic microenvironment. Similar to VacA, the EHEC-Vac-mediated vacuolisation is both prevented and reverted by the vacuolar proton pump inhibitor bafilomycin A1, suggesting a similar mechanism of vacuole formation by these toxins. Despite the similarity of phenotypes elicited by EHEC-Vac and VacA, genomic DNA from the EHEC-Vac-producing strain failed to hybridise to a vacA probe, as well as to probes derived from presently known E. coli vacuolating toxins.Through its microvascular endothelium-injuring potential combined with the ability to induce interleukin 6 release from these cells EHEC-Vac might contribute to the pathogenesis of HUS.

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Barabutis, Nektarios, Mohammad S. Akhter, Mohammad A. Uddin, Khadeja-Tul Kubra, and Andrew V. Schally. "GHRH Antagonists Protect Against Hydrogen Peroxide-Induced Breakdown of Brain Microvascular Endothelium Integrity." Hormone and Metabolic Research 52, no. 05 (May 2020): 336–39. http://dx.doi.org/10.1055/a-1149-9347.

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AbstractGrowth hormone releasing hormone is a hypothalamic neuropeptide, which regulates the release of growth hormone from the anterior pituitary gland. Growth hormone releasing hormone antagonists are anticancer agents, associated with strong anti-inflammatory activities. In the present study, we investigated the effects of the GHRH antagonist MIA-602 in the integrity of the brain microvascular endothelium in vitro. Our observations suggest that MIA-602 protects against the H2O2-induced breakdown of the brain endothelium and enhances its integrity by inducing P53, deactivating cofilin, and suppressing the RhoA inflammatory pathway. Thus, GHRH antagonists may offer an exciting possibility for the treatment of pathologies related to the blood brain barrier dysfunction, including the Parkinson’s and Alzheimer’s diseases.

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Coelho, Sharton V. A., Naiara M. Rust, Lucas Vellasco, Michelle P. Papa, Aline S. G. Pereira, Matheus Ferreira da Silva Palazzo, Maria Aparecida Juliano, et al. "Contact System Activation in Plasma from Dengue Patients Might Harness Endothelial Virus Replication through the Signaling of Bradykinin Receptors." Pharmaceuticals 14, no. 1 (January 12, 2021): 56. http://dx.doi.org/10.3390/ph14010056.

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Since exacerbated inflammation and microvascular leakage are hallmarks of dengue virus (DENV) infection, here we interrogated whether systemic activation of the contact/kallikrein-kinin system (KKS) might hamper endothelial function. In vitro assays showed that dextran sulfate, a potent contact activator, failed to generate appreciable levels of activated plasma kallikrein (PKa) in the large majority of samples from a dengue cohort (n = 70), irrespective of severity of clinical symptoms. Impaired formation of PKa in dengue-plasmas correlated with the presence of cleaved Factor XII and high molecular weight kininogen (HK), suggesting that the prothrombogenic contact system is frequently triggered during the course of infection. Using two pathogenic arboviruses, DENV or Zika virus (ZIKV), we then asked whether exogenous BK could influence the outcome of infection of human brain microvascular endothelial cells (HBMECs). Unlike the unresponsive phenotype of Zika-infected HBMECs, we found that BK, acting via B2R, vigorously stimulated DENV-2 replication by reverting nitric oxide-driven apoptosis of endothelial cells. Using the mouse model of cerebral dengue infection, we next demonstrated that B2R targeting by icatibant decreased viral load in brain tissues. In summary, our study suggests that contact/KKS activation followed by BK-induced enhancement of DENV replication in the endothelium may underlie microvascular pathology in dengue.

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Rom, Slava, Viviana Zuluaga-Ramirez, Holly Dykstra, Nancy L. Reichenbach, Servio H. Ramirez, and Yuri Persidsky. "Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions." Journal of Cerebral Blood Flow & Metabolism 35, no. 1 (September 24, 2014): 28–36. http://dx.doi.org/10.1038/jcbfm.2014.167.

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Blood—brain barrier (BBB) dysfunction seen in neuroinflammation contributes to mortality and morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. Identification of molecular targets maintaining barrier function is of clinical relevance. We used a novel in vivo model of localized aseptic meningitis where tumor necrosis factor alpha (TNFα) was introduced intracerebrally and surveyed cerebral vascular changes and leukocyte—endothelium interactions by intravital videomicroscopy. Poly(ADP-ribose) polymerase-1 (PARP) inhibition significantly reduced leukocyte adhesion to and migration across brain endothelium in cortical microvessels. PARP inactivation diminished BBB permeability in an in vivo model of systemic inflammation. PARP suppression in primary human brain microvascular endothelial cells (BMVEC), an in vitro model of BBB, enhanced barrier integrity and augmented expression of tight junction proteins. PARP inhibition in BMVEC diminished human monocyte adhesion to TNFα-activated BMVEC (up to 65%) and migration (80–100%) across BBB models. PARP suppression decreased expression of adhesion molecules and decreased activity of GTPases (controlling BBB integrity and monocyte migration across the BBB). PARP inhibitors down-regulated expression of inflammatory genes and dampened secretion of pro-inflammatory factors increased by TNFα in BMVEC. These results point to PARP suppression as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation.

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Mone, Pasquale, Jessica Gambardella, Xujun Wang, Stanislovas S. Jankauskas, Alessandro Matarese, and Gaetano Santulli. "miR-24 Targets the Transmembrane Glycoprotein Neuropilin-1 in Human Brain Microvascular Endothelial Cells." Non-Coding RNA 7, no. 1 (February 2, 2021): 9. http://dx.doi.org/10.3390/ncrna7010009.

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Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro blood–brain barrier model.

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Tripathi, Abhai K., David J. Sullivan, and Monique F. Stins. "Plasmodium falciparum-Infected Erythrocytes Increase Intercellular Adhesion Molecule 1 Expression on Brain Endothelium through NF-κB." Infection and Immunity 74, no. 6 (June 2006): 3262–70. http://dx.doi.org/10.1128/iai.01625-05.

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ABSTRACT Sequestration of Plasmodium falciparum-infected erythrocytes (Pf-IRBC) in postcapillary brain endothelium is a hallmark of cerebral malaria (CM) pathogenesis. There is a correlation between adherent Pf-IRBC and increased expression of intercellular cell adhesion molecule 1 (ICAM-1), which is also a receptor for Pf-IRBC on human brain microvascular endothelial cells (HBMEC). The underlying mechanism for the increased ICAM-1 expression has not been clearly defined. Therefore, we investigated the mechanisms of ICAM-1 expression on isolated HBMEC after exposure to Pf-IRBC. Ultrastructural characterization of the model confirmed that there was attachment through both Pf-IRBC knobs and HBMEC microvillus protrusions. Pf-IRBC induced a dose- and time-dependent increase in ICAM-1 expression on HBMEC that was specific for human brain endothelium and was not observed with human umbilical vein endothelium. Involvement of both membrane-associated Pf-IRBC proteins and parasite-derived soluble factors with the increase in ICAM-1 expression was demonstrated by surface trypsinization and fractionation. Pf-IRBC exposure induced nuclear translocation of NF-κB in HBMEC, which was linked to ICAM-1 expression, as shown by use of specific inhibitors of the transcription factor NF-κB and immunocytochemistry. In addition, inhibition of reactive oxygen species decreased Pf-IRBC-induced ICAM-1 expression on HBMEC. Parasite-induced ICAM-1 expression explains the localization of this molecule on brain endothelium in postmortem CM brain samples. By increasing ICAM-1 expression, Pf-IRBC may increase their sequestration, thereby perpetuating CM.

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OLESEN, S. P. "Free oxygen radicals decrease electrical resistance of microvascular endothelium in brain." Acta Physiologica Scandinavica 129, no. 2 (February 1987): 181–87. http://dx.doi.org/10.1111/j.1748-1716.1987.tb08057.x.

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Akhter, Mohammad S., Mohammad A. Uddin, Khadeja-Tul Kubra, and Nektarios Barabutis. "P53-induced reduction of lipid peroxidation supports brain microvascular endothelium integrity." Journal of Pharmacological Sciences 141, no. 1 (September 2019): 83–85. http://dx.doi.org/10.1016/j.jphs.2019.09.008.

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Bacic, F., S. Uematsu, R. M. McCarron, and M. Spatz. "Prostaglandin D2 in cultured capillary and microvascular endothelium of human brain." Prostaglandins, Leukotrienes and Essential Fatty Acids 46, no. 3 (July 1992): 231–34. http://dx.doi.org/10.1016/0952-3278(92)90076-u.

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DeCastro, Ariana Joy L., Lauren Griffith, and Kimberly Stroka. "Abstract B010: The effects of tumor cell-secreted factors on endothelial cell junction phenotype." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): B010. http://dx.doi.org/10.1158/1538-7445.metastasis22-b010.

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Abstract Triple negative breast cancer (TNBC) is subtype of breast cancer that has no expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC metastasizes to specific tissues such as brain and bone in a process termed organotropism. In this process, TNBC cells cross the vascular endothelium; transport across endothelial cells is, in part, regulated by cell-cell junctions. The TNBC cell secretome has been shown to contain factors such as vascular growth factor (VEGF) and matrix metalloproteinases (MMPs) that could play a role in altering endothelium permeability. Prior work by us has shown that VEGF in tumor conditioned media can alter endothelial cell junction phenotype in human brain microvascular endothelial cells. Given the various factors present in tumor conditioned media (TCM), we hypothesized that both VEGF and MMPs are present at distinct levels in conditioned media derived from brain- or bone-seeking TNBC cells and that these factors alter junction phenotype in human umbilical vein endothelial cells. We quantified levels of VEGF and MMPs 1 and 9 in tumor conditioned media from parental, brain-seeking, and bone-seeking MDA-MB-231 cells. Our results show that brain-seeking tumor cell conditioned media reduces VE-cadherin continuous junction coverage compared to conditioned media from parental or bone-seeking cells. VE-Cadherin junctions also have decreased junction widths in response to tumor conditioned treatment from brain-seeking MDAs. These results show that secreted factors from TNBC cells have a modest impact on endothelium junction integrity, and future work will quantify changes in endothelium permeability to test barrier function. This work will contribute to a further understanding of TNBC organotropic metastasis and more effective targeted therapeutics to prevent disease progression. Citation Format: Ariana Joy L. DeCastro, Lauren Griffith, Kimberly Stroka. The effects of tumor cell-secreted factors on endothelial cell junction phenotype [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B010.

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Bernstein, David L., Viviana Zuluaga-Ramirez, Sachin Gajghate, Nancy L. Reichenbach, Boris Polyak, Yuri Persidsky, and Slava Rom. "miR-98 reduces endothelial dysfunction by protecting blood–brain barrier (BBB) and improves neurological outcomes in mouse ischemia/reperfusion stroke model." Journal of Cerebral Blood Flow & Metabolism 40, no. 10 (October 10, 2019): 1953–65. http://dx.doi.org/10.1177/0271678x19882264.

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Most neurological diseases, including stroke, lead to some degree of blood–brain barrier (BBB) dysfunction. A significant portion of BBB injury is caused by inflammation, due to pro-inflammatory factors produced in the brain, and by leukocyte engagement of the brain endothelium. Recently, microRNAs (miRNAs) have appeared as major regulators of inflammation-induced changes to gene expression in the microvascular endothelial cells (BMVEC) that comprise the BBB. However, miRNAs’ role during cerebral ischemia/reperfusion is still underexplored. Endothelial levels of miR-98 were significantly altered following ischemia/reperfusion insults, both in vivo and in vitro, transient middle cerebral artery occlusion (tMCAO), and oxygen–glucose deprivation (OGD), respectively. Overexpression of miR-98 reduced the mouse’s infarct size after tMCAO. Further, miR-98 lessened infiltration of proinflammatory Ly6CHI leukocytes into the brain following stroke and diminished the prevalence of M1 (activated) microglia within the impacted area. miR-98 attenuated BBB permeability, as demonstrated by changes to fluorescently-labeled dextran penetration in vivo and improved transendothelial electrical resistance (TEER) in vitro. Treatment with miR-98 improved significantly the locomotor impairment. Our study provides identification and functional assessment of miRNAs in brain endothelium and lays the groundwork for improving therapeutic approaches for patients suffering from ischemic attacks.

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Vorbrodt, A. W., and R. S. Trowbridge. "Ultracytochemical characteristics of cultured goat brain microvascular endothelial cells [corrected]." Journal of Histochemistry & Cytochemistry 39, no. 11 (November 1991): 1555–63. http://dx.doi.org/10.1177/39.11.1655877.

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This ultrastructural study was undertaken to determine the localization of cytochemically demonstrable blood-brain barrier (BBB)-associated enzymatic activities and of some nonenzymatic constituents in goat [corrected] brain microvascular endothelial cells (ECs) growing in vitro. Positive reactions for alkaline phosphatase (AP), 5'-nucleotidase (5'N), transport ATPase (Na+,K(+)-ATPase), and adenosine diphosphatase (ADPase) were present on both apical and basolateral plasma membranes (PMs) of the ECs. The reaction for calcium-dependent ATPase (Ca(2+)-ATPase) was less intense and was restricted to basolateral PM and associated plasmalemmal pits. These cells also revealed an abundance of anionic sites labeled with cationic colloidal gold (CCG) and Ricinus communis agglutinin 120 (RCA)-binding sites, specific for beta-D-galactosyl residues, on the apical PM. The labeling of the apical PM with Ulex europaeus agglutinin (UEA)-gold complex, specific for alpha-L-fucosyl residues, was negligible. When compared with results of cytochemical examination of the ECs of goat [corrected] brain capillary in vivo, these observations indicate that although cells cultivated in vitro retain at confluence the enzymatic activities typical for BBB-type ECS, they lose their characteristic (polar) localization. This loss is interpreted as a reflection of lost functional polarity of the microvascular endothelium in vitro resulting from deprivation of the normal influence of the components of brain parenchyma.

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Hawkins, Brian T., Richard D. Egleton, and Thomas P. Davis. "Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 1 (July 2005): H212—H219. http://dx.doi.org/10.1152/ajpheart.01210.2004.

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Nicotine increases the permeability of the blood-brain barrier in vivo. This implies a possible role for nicotinic acetylcholine receptors in the regulation of cerebral microvascular permeability. Expression of nicotinic acetylcholine receptor subunits in cerebral microvessels was investigated with immunofluorescence microscopy. Positive immunoreactivity was found for receptor subunits α3, α5, α7, and β2, but not subunits α4, β3, or β4. Blood-brain barrier permeability was assessed via in situ brain perfusion with [14C]sucrose. Nicotine increased the rate of sucrose entry into the brain from 0.3 ± 0.1 to 1.1 ± 0.2 μl·g−1·min−1, as previously described. This nicotine-induced increase in blood-brain barrier permeability was significantly attenuated by both the blood-brain barrier-permeant nicotinic antagonist mecamylamine and the blood-brain barrier-impermeant nicotinic antagonist hexamethonium to 0.5 ± 0.2 and 0.3 ± 0.2 μl·g−1·min−1, respectively. These data suggest that nicotinic acetylcholine receptors expressed on the cerebral microvascular endothelium mediate nicotine-induced changes in blood-brain barrier permeability.

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Rigor, Robert R., Richard S. Beard, Olesya P. Litovka, and Sarah Y. Yuan. "Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium." American Journal of Physiology-Cell Physiology 302, no. 10 (May 15, 2012): C1513—C1522. http://dx.doi.org/10.1152/ajpcell.00371.2011.

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Blood-brain barrier dysfunction is a serious consequence of inflammatory brain diseases, cerebral infections, and trauma. The proinflammatory cytokine interleukin (IL)-1β is central to neuroinflammation and contributes to brain microvascular leakage and edema formation. Although it is well known that IL-1β exposure directly induces hyperpermeability in brain microvascular endothelium, the molecular mechanisms mediating this response are not completely understood. In the present study, we found that exposure of the human brain microvascular endothelium to IL-1β triggered activation of novel PKC isoforms δ, μ, and θ, followed by decreased transendothelial electrical resistance (TER). The IL-1β-induced decrease in TER was prevented by small hairpin RNA silencing of PKC-θ or by treatment with the isoform-selective PKC inhibitor Gö6976 but not by PKC inhibitors that are selective for all PKC isoforms other than PKC-θ. Decreased TER coincided with increased phosphorylation of regulatory myosin light chain and with increased proapoptotic signaling indicated by decreased uptake of mitotracker red in response to IL-1β treatment. However, neither of these observed effects were prevented by Gö6976 treatment, indicating lack of causality with respect to decreased TER. Instead, our data indicated that the mechanism of decreased TER involves PKC-θ-dependent phosphorylation of the tight junction protein zona occludens (ZO)-1. Because IL-1β is a central inflammatory mediator, our interpretation is that inhibition of PKC-θ or inhibition of ZO-1 phosphorylation could be viable strategies for preventing blood-brain barrier dysfunction under a variety of neuroinflammatory conditions.

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d’Uscio, Livius V., Tongrong He, Anantha V. Santhanam, and Zvonimir S. Katusic. "Endothelium-specific amyloid precursor protein deficiency causes endothelial dysfunction in cerebral arteries." Journal of Cerebral Blood Flow & Metabolism 38, no. 10 (September 29, 2017): 1715–26. http://dx.doi.org/10.1177/0271678x17735418.

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The exact physiological function of amyloid-β precursor protein (APP) in endothelial cells is unknown. Endothelium-specific APP-deficient (eAPP−/−) mice were created to gain new insights into the role of APP in the control of vascular endothelial function. Endothelium-dependent relaxations to acetylcholine were significantly impaired in basilar arteries of global APP knockout (APP−/−) and eAPP−/− mice ( P < 0.05). In contrast, endothelium-independent relaxations to nitric oxide (NO)-donor diethylamine-NONOate were unchanged. Western blot analysis revealed that protein expression of endothelial nitric oxide synthase (eNOS) was significantly downregulated in large cerebral arteries of APP−/− mice and eAPP−/− mice as compared to respective wild-type littermates ( P < 0.05). Furthermore, basal levels of cyclic guanosine monophosphate (cGMP) were also significantly reduced in large cerebral arteries of APP-deficient mice ( P < 0.05). In contrast, protein expression of prostacyclin synthase as well as levels of cyclic adenosine monophosphate (cAMP) was not affected by genetic inactivation of APP in endothelial cells. By using siRNA to knockdown APP in cultured human brain microvascular endothelial cells we also found a significant downregulation of eNOS mRNA and protein expressions in APP-deficient endothelium ( P < 0.05). These findings indicate that under physiological conditions, expression of APP in cerebral vascular endothelium plays an important protective function by maintaining constitutive expression of eNOS .

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Tagaya, Masafumi, Hans-Peter Haring, Ingrid Stuiver, Simone Wagner, Takeo Abumiya, Jacinta Lucero, Pauline Lee, Brian R. Copeland, Dietmar Seiffert, and Gregory J. del Zoppo. "Rapid Loss of Microvascular Integrin Expression during Focal Brain Ischemia Reflects Neuron Injury." Journal of Cerebral Blood Flow & Metabolism 21, no. 7 (July 2001): 835–46. http://dx.doi.org/10.1097/00004647-200107000-00009.

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The integrity of cerebral microvessels requires the close apposition of the endothelium to the astrocyte endfeet. Integrins α1β1 and α6β4 are cellular matrix receptors that may contribute to cerebral microvascular integrity. It has been hypothesized that focal ischemia alters integrin expression in a characteristic time-dependent manner consistent with neuron injury. The effects of middle cerebral artery occlusion (MCAO) and various periods of reperfusion on microvasclar integrin α1β1 and α6β4 expression were examined in the basal ganglia of 17 primates. Integrin subunits α1 and β1 colocalized with the endothelial cell antigen CD31 in nonischemic microvessels and with glial fibrillary acidic protein on astrocyte fibers. Rapid, simultaneous, and significant disappearance of both integrin α1 and β1 subunits and integrin α6β4 occurred by 2 hours MCAO, which was greatest in the region of neuron injury (ischemic core, Ic), and progressively less in the peripheral (Ip) and nonischemic regions (N). Transcription of subunit β1 mRNA on microvessels increased significantly in the Ic/Ip border and in multiple circular subregions within Ic. Microvascular integrin α1β1 and integrin α6β4 expression are rapidly and coordinately lost in Ic after MCAO. With loss of integrin α1β1, multiple regions of microvascular β1 mRNA up-regulation within Ic suggest that microvessel responses to focal ischemia are dynamic, and that multiple cores, not a single core, are generated. These changes imply that microvascular integrity is modified in a heterogeneous, but ordered pattern.

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Journal articles on the topic 'Brain microvascular endothelium'

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