Literatura académica sobre el tema "VEGF, HYPERTENSION"

Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function and modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling before birth. To determine whether lung VEGF expression is decreased in an experimental model of persistent pulmonary hypertension of the newborn (PPHN), we measured lung VEGF and VEGF receptor protein content from fetal lambs 7–10 days after ductus arteriosus ligation (132–140 days gestation; term = 147 days). In contrast with the surge in lung VEGF expression during late gestation in controls, chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78%. To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits VEGF165. Compared with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and pulmonary vascular resistance by 22 and 50%, respectively, caused right ventricular hypertrophy, and increased wall thickness of small pulmonary arteries. EYE001 treatment reduced lung endothelial nitric oxide synthase protein content by 50% and preferentially impaired the pulmonary vasodilator response to ACh, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression and that selective inhibition of VEGF165 mimics the structural and physiological changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developing lung and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.

The aim of the present study was to determine the expression of vascular endothelial growth factor (VEGF) family receptors (VEGFR) in placentas from pregnancies complicated by hypertensive disorders of different clinical severity. Placental tissue from women with gestational hypertension, pre-eclampsia, pre-eclampsia with haemolysis, elevated liver enzymes and low platelets (HELLP syndrome) and normotensive women, as a control group, was examined. Immunohistochemical techniques, reverse transcription–polymerase chain reaction and western blot were used to evaluate receptor expression. In cases with gestational hypertension, as well as in control cases, VEGFR-1 and VEGFR-3 immunoreactivity was detected in all placental components, whereas in placentas from the pre-eclampsia and pre-eclampsia with HELLP syndrome groups, VEGFR-1 and VEGFR-3 immunoreactivity was detected only in some portions of trophoblast and/or some vessels and/or clusters of stromal cells. In the control group, VEGFR-2 immunoreactivity was observed only in the vessels, whereas the hypertensive groups showed VEGF-2 immunoreactivity also in trophoblast and stromal cells. The mRNA levels of the three receptors in the group with gestational hypertension were higher with respect to those in the control group. Placentas from pregnancies with pre-eclampsia showed lowest mRNA expression levels, whereas placentas from women with pre-eclampsia plus HELLP syndrome showed higher mRNA expression levels with respect to the three other groups. Receptor protein levels were lower in pathological cases compared with levles in the control group. These findings demonstrate a dysregulation of placental expression of VEGF family receptors related to the degree of clinical severity of the hypertensive disorder.

One of the key regulators of vascular tone is the vascular endothelial growth factor (VEGF), which can enhance the production of nitric oxide, a potent vasodilator, and reduce vascular resistance by generating new vessels. Both mechanisms contribute to blood pressure decrease. The implementation of a new class of antitumor therapy — inhibitors of VEGF signaling pathway — results in the growth of cardiovascular complications such as arterial hypertension (HTN). The paper analyzes the causes of HTN development, approaches to the timely diagnosis of HTN and the correct assessment of cardiovascular risk before administration of VEGF inhibitors and during the treatment. We also review the features of the approaches of elevated blood pressure management in patients receiving targeted therapy.

Angiogenic factors exert protective effects on the lung. To investigate the effect of VEGF-B, a factor coexpressed in the lung with VEGF-A, we assessed chronic hypoxic pulmonary hypertension in VEGF-B knockout mice (VEGF-B−/−) and in rats with lung overexpression of VEGF-B induced by adenovirus transfer. No significant difference in pulmonary hemodynamics, right ventricular hypertrophy, distal vessel muscularization, or vascular density was found between VEGF-B−/− and control mice after 3 wk of hypoxia. When overexpressed, VEGF-B167 or VEGF-B186 had protective effects similar to those of human VEGF-A165. Lung endothelial nitric oxide synthase (eNOS) expression was increased by 5 days of hypoxia or VEGF-A adenovirus vector (Ad.VEGF-A) overexpression, whereas VEGF-B167 or VEGF-B186had no effect. With hypoxia or normoxia, the wet-to-dry lung weight ratio was increased 5 days after Ad.VEGF-A administration compared with control (Ad.nul), Ad.VEGF-B167, or Ad.VEGF-B186. Endogenous VEGF-B does not counteract the development of hypoxic pulmonary hypertension. However, when overexpressed in the lung, VEGF-B can be as potent as VEGF-A in attenuating pulmonary hypertension, although it has no effect on eNOS expression or vascular permeability.

Neoangiogenesis is a critical phenomenon enabling the growth and metastasis of tumors, and inhibitors of neoangiogenesis have been recently added to the armamentarium of anticancer therapies available for clinical use. Dysregulated signaling through the vascular endothelial growth factor (VEGF) pathway has been implicated as a key mediator of neoangiogenesis in tumors. Agents that block signaling through the VEGF pathway demonstrated tumor shrinkage in preclinical models and were therefore developed as anticancer therapies for use in humans. VEGF kinase inhibitors are being used in the treatment of a wide variety of cancers, and recent studies have shown that patients will likely require long-term treatment with these agents. Hypertension has emerged as a frequent side effect associated with agents that block signaling through the VEGF pathway. A thorough understanding of the mechanisms underlying hypertension is crucial to developing appropriate therapeutic strategies for treating hypertension associated with VEGF kinase inhibitors. Several recent studies have advanced our understanding of the pathophysiology of hypertension associated with VEGF kinase inhibitors and will be the subject of this review.

Bevacizumab is a humanised monoclonal antibody targeted to the vascular endothelial growth factor (VEGF). VEGF is the ligand for VEGF receptors (VEGFR), which are important for the development and maintenance of the angiogenic phenotype in high-grade solid tumors, including malignant gliomas. An overview of angiogenesis, VEGF, VEGFR, and the pharmacology of bevacizumab will be presented. Bevacizumab is active in pre-clinical testing against glioma tissue cultures and xenograft models. In the clinical setting, in combination with irinotecan and other chemotherapy agents, it has shown significant activity in patients with glioblastoma multiforme (GBM) and other brain tumors. Objective responses on neuro-imaging have been noted in 30%-60% of reported cases. Prolongation of progression-free survival and overall survival have also been suggested in many reports. Treatment of bevacizumab is associated with potential side effects, including thromboembolic disorders, fatigue, intracranial hemorrhage, proteinuria, hypertension, and bowel perforation.

To determine whether disruption of vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling in the newborn has long-term effects on lung structure and function, we injected 1-day-old newborn rat pups with a single dose of Su-5416, a VEGFR inhibitor, or vehicle (controls). Lungs from infant (3-wk-old) and adult (3- to 4-mo-old) rats treated with Su-5416 as newborns showed reductions in arterial density (82 and 31%, respectively) and alveolar counts (45 and 29%) compared with controls. Neonatal treatment with Su-5416 increased right ventricle weight to body wt ratios (4.2-fold and 2.0-fold) and pulmonary arterial wall thickness measurements (2.7-fold and 1.6-fold) in infant and adult rats, respectively, indicating marked pulmonary hypertension. We conclude that treatment of newborn rats with the VEGFR inhibitor Su-5416 impaired pulmonary vascular growth and postnatal alveolarization and caused pulmonary hypertension and that these effects were long term, persisting well into adulthood.

Recent studies have shown that the tonicity-responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway-induced lymphangiogenesis provides a buffering mechanism for high salt (HS) intake-induced elevation of blood pressure (BP). Moreover, blocking of TonEBP/VEGF-C signaling by mononuclear phagocyte depletion can induce salt-sensitive hypertension in rats. We hypothesized that HS intake could have an impact on cardiac lymphangiogenesis, and regulation of VEGF-C bioactivity, which is largely through the main receptor for VEGFR-3, may modulate HS intake-induced left ventricular remodeling. We demonstrated upregulation of TonEBP, increased macrophage infiltration, and enhanced lymphangiogenesis in the left ventricles of spontaneously hypertensive rats (SHR) that were fed a HS diet (8.0% NaCl). Then, retrovirus vectors capable of overexpression (ΔNΔC/VEGF-C/Cys152Ser, used for overexpressing VEGF-C) and blocking (VEGFR-3-Rg, used for trapping of bioactive VEGF-C) of VEGF-C and control vector (pLPCX) were intravenously administered to SHR from week 9 of a 12-wk HS loading period. At the end of the HS challenge, overexpression of VEGF-C led to enhanced cardiac lymphangiogenesis, decreased myocardial fibrosis, and macrophage infiltration, preserved left ventricular functions, as well as decreased blood pressure level compared with the HS group and the control vector-treated HS group. In contrast, systemic blocking of VEGF-C was associated with elevation of blood pressure level and an exacerbation of hypertensive left ventricular remodeling, as indicated by increased fibrosis and macrophage infiltration, and diminished lymphangiogenesis. Hence, our findings highlight that VEGF-C/VEGFR-3 is a promising therapeutic target to attenuate hypertensive left ventricular remodeling induced by HS intake, presumably via blood pressure-dependent and -independent mechanisms.

Le VEGF-A est impliqué dans plusieurs pathologies, dont les maladies cardiovasculaires et plusieurs types de cancer. L'existence de voies de signalisation communes entre le VEGF-A, les molécules d'adhésion cellulaire et des molécules de l'inflammation pourrait permettre d'expliquer la large gamme de fonctions du VEGF-A dans les différentes situations pathologiques. Dans le cadre de cette thèse, nous avons développé une approche intégrative pour l’étude du VEGF-A et de son positionnement au sein de plusieurs voies métaboliques. Cette approche associe les études d’identification des variants génétiques associés au VEGF-A et leur fonctionnalité biologique par une approche transcriptomique. Ainsi, le but général de cette thèse est d’investiguer les relations complexes des polymorphismes liés au VEGF-A, des taux plasmatiques et de l’expression du VEGF-A avec les molécules d'adhésion cellulaire et les molécules de l’inflammation, les lipides plasmatiques, les gènes candidats NOS3, CD14, MMP3 et IL4, et avec les facteurs de risque cardiovasculaires (obésité, pression artérielle) chez des individus en bonne santé. Pour la réalisation de ces études, nous avons utilisé des sous-groupes de populations de la cohorte STANISLAS et autres populations du Centre de Ressources Biologiques IGE-PCV. L’expérimentation transcriptomique est réalisée avec des cellules mononucléaires du sang périphérique.Parmi les résultats obtenus nous avons montré : • Une association entre l'isoforme VEGF-A145 et l'ARNm d'ICAM-1, de sélectine L et de TNF-α. • Une association entre les taux du VEGF-A et les taux d’ICAM-1 et de la sélectine E. • Des interactions épistatiques entre les variants du VEGF-A pour les taux de la sélectine E, du TNF-α, de l'ICAM-1 et de l'IL-6. • Une association significative entre rs4416670 et les niveaux de l'ARNm de la sélectine-L • Une association entre le variant rs6921438 et les niveaux de HDL-C et LDL-C. • Une interaction entre rs4416670 et hypertension pour la variation interindividuelle de l'apolipoprotéine E. • Des associations significatives entre l’expression de l’isoforme VEGF-A145 et les polymorphismes de NOS3, CD14, MMP3, IL4R, et IL4. • Des interactions épistatiques significatives entre les variants génétiques de NOS3, CD14, MMP3, IL4R, et IL4 et les quatre polymorphismes liés au VEGF-A sur les taux plasmatiques de VEGF-A. • Des interactions significatives entre le rs1800779 de NOS3 et HDL-C, les triglycérides et l’obésité ainsi que l’interaction de rs6921438 avec l’hypertension pour les niveaux plasmatique de VEGF-A • Des associations significatives et interactions gène × lipides du sang entre tous les variants génétiques de VEGF-A et les phénotypes d’obésité. • Une association significative entre le rs4416670 et la pression pulsée. • Une interaction épistatique entre le rs6921438 et le rs10738760 pour la pression pulsée. • Des associations significatives entre le variant rs10738760 de VEGF-A et le risque de syndrome métabolique. Les résultats de cette thèse montrent le rôle central du VEGF-A dans la régulation des différents processus physiologiques et permettant de proposer le VEGF-A comme un nouveau biomarqueur potentiel des maladies cardiovasculaires à évaluer cliniquement
VEGF-A is involved in several diseases, including cardiovascular disease and several types of cancer. The existence of common signaling between the VEGF-A, cell adhesion molecules and inflammatory molecules may help to explain the wide range of functions of VEGF-A in different pathological situations. As part of this thesis, we have developed an integrative approach to study of VEGF-A and its position in several metabolic pathways. This approach involves the identification of genetic variants associated with VEGF-A and their biological function by a transcriptomic approach. Thus, the general aim of this thesis is to investigate the complex relationships between four polymorphisms associated with VEGF-A, its plasma levels and its expression with cell adhesion molecules, inflammatory molecules, plasma lipids, candidate genes (NOS3, CD14, MMP3 and IL-4) and with cardiovascular risk factors (obesity and blood pressure) in healthy individuals. For our studies, we used a subgroup of the STANISLAS Family Study and other populations available in the Biological Resources Center IGE-PCV. Our transcriptomics experiments have been performed with peripheral blood mononuclear cells. The results showed: • An association between VEGF-A145 isoform with the levels of ICAM-1 mRNA, L-selectin mRNA and TNF-α mRNA. • An association between the levels of VEGF-A and the levels of ICAM-1 and E selectin. • An epistatic interactions between the VEGF-A related variants for the levels of E selectin, TNF-α], ICAM-1 and IL-6. • An association of rs4416670 with levels of mRNA of L selectin. • An association between rs6921438 and levels of HDL-C and LDL-C. • An interaction between rs4416670 and hypertension for the interindividual variation of apolipoprotein E. • Significant associations between the expression of VEGF-A with NOS3, CD14, MMP3, IL4R and IL-4 polymorphisms. • Significant epistatic interactions between genetic variants of NOS3, CD14, MMP3, IL4R, and IL4 and the four polymorphisms related to VEGF-A on the plasma levels of VEGF-A. • Significant interactions between rs1800779 in NOS3 and HDL-C, triglycerides, and obesity, as well as interactions of rs6921438 with hypertension on plasma levels of VEGF-A. • Significant associations and gene × blood lipids interactions between all genetic variants of VEGF-A with obesity traits. • A significant association between rs4416670 and pulse pressure. • An epistatic interaction between rs6921438 and rs10738760 on pulse pressure. • Significant associations between the rs10738760 variant of VEGF-A and the risk of metabolic syndrome. The results of this thesis indicate the central role of VEGF-A in the regulation of various physiological processes and offer VEGF-A as a potential novel biomarker for cardiovascular disease to be further evaluated clinically

Kinesiology
Ph.D.
Purpose: Translational research characterizing endothelial dysfunction and the progression of cardiovascular disease (CVD) is necessary for understanding the complex nature of multi-factorial diseases. Perhaps more important though, is understanding the compensatory and adaptive processes associated with regression of diseases and chronic oxidative stress. Vascular endothelial growth factor (VEGF) is an important protein in endothelial health and nitric oxide (NO) production. The purpose of this research was to examine changes in VEGF-mediated endothelial nitric oxide synthase (eNOS) activity under conditions of oxidative stress both in vivo and in vitro. Methods: The oxidative stress relationship involving plasma VEGF, NO, and hydrogen peroxide (H2O2) was assessed in sedentary, pre-hypertensive African American participants both (n=48) before and following (n=22) 6 months of aerobic exercise training (AEXT). In vitro, H2O2 exposure along with atherogenic, 4 dyne/cm2, and athero-protective, 20 dyne/cm2, levels of laminar shear stress (LSS) were used to characterize VEGF-mediated eNOS activity to gain insights into physiological signaling. Results: At baseline, VEGF levels increased with increasing blood pressure (BP) level while NO levels decreased from normotensive to hypertensive participants. H2O2 levels also trended upward with increasing BP level, and in vitro H2O2 was observed to decrease VEGF-mediated eNOS activity in a dose dependent manner. Following AEXT, participants were divided into groups relative to their BP change following the intervention. Participants that decreased their BP level demonstrated a decrease in VEGF and H2O2 level. In addition, following 24 hrs of LSS at 20 dyne/cm2, VEGF-mediated eNOS activity and VEGFR2 protein expression was significantly lower compared to 24 hrs of LSS at 4 dyne/cm2. Discussion: Increased circulating levels of VEGF in vivo may be a compensatory mechanism. Endothelial dysfunction and progressive CVD may trigger such compensation. The adaptive response to exercise for its BP-lowering effects is systemic and encompasses many changes. These beneficial adaptations have likely alleviated the compensatory mechanism of elevated VEGF levels seen at baseline. Indeed, following 24 hrs of an athero-protective LSS level, VEGF-mediated eNOS activity was significantly lower compared to 24 hr of LSS at an atherogenic level. The difference in VEGF-mediated eNOS activity may be due, in part, to the decrease in VEGFR2 protein expression we observed under an athero-protective LSS level.
Temple University--Theses

Orientadores: José Antonio Rocha Gontijo, Flávia Fernandes Mesquita Vieira
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O ambiente em que vivemos tem grande influência no desenvolvimento e na vida adulta do feto, sendo que a alimentação ou o tabagismo vêem como hábitos e estilo de vida que estão diretamente relacionados a modificações na organogênese fetal. O tabagismo é um dos fatores de maior preocupação das autoridades em saúde pública, devido aos graves problemas à saúde causados pelo cigarro, os custos sociais e econômicos decorrentes destas afecções e, atualmente às possíveis implicações epigenéticas dada incidência do tabagismo em gestantes que pode repercutir sobre gerações futuras. Vários estudos tratam dos efeitos danosos e das repercussões do cigarro no organismo de gestantes e no desenvolvimento do feto, tais como hipertensão arterial, doenças cardiovasculares, maior prevalência de aborto espontâneo, morbidade intrauterina , retarde no crescimento fetal, entre outros. A inalação de monóxido de carbono (CO) pelas gestantes, através do cigarro, causa no feto um estado de hipóxia que pode ser, muitas vezes, fatal. Em resposta a este déficit de oxigênio alguns mecanismos fisiológicos podem ser observados, como: o aumento da expressão do hormônio endógeno eritropoietina (EPO) que regula a eritropoiese e consequentemente, os níveis de hemoglobina e a hematose dos tecidos. O fator induzível por hipóxia (HIF-1) atua na regulação da expressão EPO, sobre a angiogênese, e na viabilidade e proliferação celular vascular entre outras funções. Nesta emaranhada rede de estímulos, está intimamente envolvido o fator de crescimento do endotélio vascular (VEGF) que tem na hipóxia um dos principais estímulos a sua expressão. Este fator é o mais importante mediador do desenvolvimento vascular renal, principalmente do processo de diferenciação do corpúsculo glomerular. Observamos que a inalação de tabaco não modificou significativamente a evolução da massa corporal das mães durante a prenhes (figura 6). No entanto, a prole de animais submetidos ao fumo apresentou uma expressiva redução da massa corporal ao nascer - Ct 7,2± 0,05DPM g vs. Fm 6,3± 0,24DPM g (figura 7), e da nona e décima semana de vida - Ct 322± 20,5DPM g vs. Fm 286± 32,3DPM g e Ct 329± 20,4DPM g vs. Fm 294± 32,6DPM g, respectivamente (figura 8). Os resultados referente à função renal na prole Ct e Fm na 5ª semana de vida não mostraram diferenças significativas na filtração glomerular (CCr) tão pouco na reabsorção proximal de sódio. Contudo, a prole Fm apresentou um aumento significativo na excreção de sódio (FENa+ 24,5%, FEK 13,8%, FEPPNa+ 25,3% e CENa+ 20%) quando comparado ao Ct (figura 13). Por outro lado, na 10ª semana de vida, observamos um aumento significativo (p=0,01) no CCr - 13,9% e na CENa+ - 17,7%, na prole Fm vs. Ct. Nestes animais não houve diferença na reabsorção de Na+ no túbulo proximal e pós-proximal, consequentemente não observamos diferenças significativas na FENa+ e FEK (figura 14). Nos animais Fm de 13 semanas de vida nenhum dos parâmetros das provas funcionais renais se alteraram (figura 15). Contudo, estritamente nesta idade podemos observar um elevação na pressão arterial (p=0,02) entre os grupos Ct e Fm - 134± 9,79DPM mmHg e 146± 11,07DPM mmHg, respectivamente (figuras 11). Não observamos modificações significativas, através da estereologia renal, no volume renal (Ct 0,12 ±0,01 vs. Fm 0,11 ±0,004), na massa renal (Ct 0,43 ±0,03 vs. Fm 0,37 ±0,01) nos animais com 12 dias de vida. Embora, não estatisticamente significativo, a prole Fm apresentou uma redução de 10% no volume glomerular (Ct 16420 ±2411 vs. Fm 15860 ±1078) e 8,2% menos glomérulos (Ct 10450 ±2030 vs. Fm 8628 ±900) quando comparados ao Ct (figuras 16 a 19). Os resultados quantitativos das proteínas envolvidas na angiogênese e eritropoiese - VEGF e EPO, dados pelo ensaio de western blotting, não apresentaram diferenças significativas entre os grupos (figuras 20 a 22). Contudo, os resultados semi-quantitativos por imunolocalização mostrou uma elevada intensidade fluorocrômica do VEGF nos animais Fm e de HIF1? nos animais Ct no período embrionário - E17 (figuras 23 a 27). Observamos, também, uma expressiva modificação na estrutura da matriz extracelular por deposição de proteínas no sitio intersticial e perivascular renal nos animais Fm de 16 semanas vida comparadas ao Ct dadas pela histoquímica de picrossíruis e imunofluorêscencia de fibronectina (figura 29 a 32). Assim, podemos concluir que, a exposição intrauterina ao fumo e seus componentes, podem levar a uma modificação morfofuncional renal na vida adulta que reflete diretamente na manutenção da pressão arterial
Abstract: Prior study about developmental plasticity hypothesis suggests that various adverse intra-uterine exposures lead to persistent fetal developmental adaptations. Maternal smoking is a very important modifiable adverse fetal exposure in western countries and leads to a decrease in the offspring's birth weight. Thus far, the specific adverse fetal smoking exposures and mechanisms underlying these associations on renal development and functional disorder are unclear. The present study investigates, in adult male rats, the effect of smoking exposure (Sk) in utero on blood pressure (BP), and its association with nephron structure and function changes. In the current study, showed in 13-week old Sk offspring enhanced arterial blood pressure, reduced nephron number are associated with higher TGF-?1 glomerular expression. Sk glomeruli also presented an upregulated collagen and fibronectin deposition intrinsically related to fibrotic process as compared to age-matched control group. From our present knowledge, these are the first data showing renal morphological and functional modifications in the gestational smoking model of fetal programming. The fetal-programmed adult rats showed structural kidney disorders associated with a striking stage of fibrosis, which led us to state that the glomerular overflow and subsequently TGF-?1 activity inducing fibrotic protein expression that may cause glomerular EMT
Mestrado
Fisiopatologia Médica
Mestre em Ciências

Introdução: A hipertensão arterial sistêmica (HAS) é uma doença que pode determinar lesões em diversos órgãos inclusive nos olhos. As doenças vasculares oculares constituem a grande maioria das causas de cegueira na atualidade e a HAS tem contribuição importante nesta estatística. A variabilidade da pressão arterial tem sido implicada na gênese de uma série de lesões de órgãos-alvo. Na tentativa de compreender melhor a patogênese das doenças vasculares oculares testamos a hipótese de que não apenas os efeitos da HAS, mas também a variabilidade da pressão arterial (PA) poderia determinar lesão de órgão-alvo (ocular). Materiais e Métodos: A desnervação sino-aórtica (DSA), um modelo experimental de aumento da variabilidade da pressão arterial foi utilizado nos experimentos. Foram obtidas medidas da pressão intraocular e a partir destas medidas, a pressão de perfusão ocular. Foram analisados marcadores de estresse oxidativo (8-OHdG e nitrotirosina),VEGF e receptores AT1 na retina de animais normotensos e hipertensos com e sem DSA aguda (12 e 24 horas) e crônica (10 semanas). Resultados: Os animais desnervados apresentaram aumento da variabilidade da PA sem modificar a PA basal e redução da sensibilidade do barorreflexo. Houve aumento da modulação simpática vascular e da pressão de perfusão ocular (PPO), nos animais hipertensos, com aumento adicional da PPO nos hipertensos e desnervados crônicos.Observou-seestresse oxidativo retiniano nos animais desnervados agudos e noshipertensos desnervados crônicos, além do aumento da expressão de receptores AT1 da Angiotensina II nos animais hipertensos. Os níveis de VEGF retinianos dos animais desnervados crônicos, apresentaram comportamento inverso aos níveis de Caspase-3. Conclusão: Tais resultados indicam que só a HAS, mas também a variabilidade da PA podem determinar variações na pressão de perfusão ocular, assim como também podem induzir dano oxidativo às células retinianas. Além disso, pode-se sugerir efeito neuroprotetor retiniano do VEGF
Introduction: High blood pressure (HBP) is a disease that can determine lesions in many organs including the eyes. The ocular vascular diseases constitute the vast majority of causes of blindness and hypertension has important contribution in this statistic. Blood pressure variability has been implicated in the genesis of a series of end-organ damage. In an attempt to better understand the pathogenesis of ocular vascular diseases, we hypothesized that not only the effects of hypertension, but also the variability of blood pressure (BPV) could determine target end-organ damage (ocular). Materials and Methods: Sino-aortic denervation (SAD), an experimental model of increased blood pressure variability was used in the experiments. The intraocular pressure measurements were performed and from these measurements the ocular perfusion pressure was estimated. Oxidative stress markers (8-OHdG and nitrotyrosine), VEGF and AT1 receptor in rat retinas were analyzed inacute and chronic hypertensive and normotensiveSAD rats and in controls. Results: Denervated animals showed increased BP variability without altering the basal BP, while presenting reduced baroreflex sensitivity.There was an increase in sympatheticvascular modulation and in OPP,in hypertensive animals, that was additionally in chronic denervated hypertensive animals.Acute denervated and chronic hypertensive denervated animals showed retinal oxidative stress as well as hypertensive animals presented increased expression of AT1 receptors of angiotensin II. The levels of retinal VEGF of chronically denervated animals showed inverse behavior of levels of Caspase-3 Conclusion: These results suggest that, apart from the arterial hypertension, BP variability not only determines changes in ocular perfusion pressure, but also induces oxidative damage to retinal cells. Furthermore, one can suggest retinal neuroprotective effect of VEGF

碩士
高雄醫學大學
藥理學研究所
96
The endothelial dysfunction resulting in vessel contraction observed in hypertension appears to be a consequence of high blood pressure. In normal endothelial cell, activation of endothelial nitric oxide synthase (eNOS), soluble guanylyl cyclase (sGC) and protein kinase G (PKG) resulted in vasodilation and anti-hypertension. Our previous studies have demonstrated that KMUP-1, a unique xanthine and piperazine derivative, activated the NO/ sGC/ cGMP pathway, and could lead to vascular relaxation. We used 8 week-old Spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rat for our experimental model. In the present study, the experimental rats were subdivided into five groups：(1) W1 (WKY group 1：control), (2) W2 [WKY group 2：treating with KMUP-1 (10 mg/kg)], (3) S1 (SHR group 1：control), (4) S2 [SHR group 2：treating with KMUP-1 (10 mg/kg)], (5) S3 [SHR group 3：treating with KMUP-1 (30 mg/kg)]. During 28 days of treatments, systolic blood pressure (SBP) was measured weekly to confirm whether KMUP-1 could ameliorate SBP in SHR. Furthermore, we used aorta to check eNOS, sGCα1, PKG protein expression by Western blotting.Our results showed that SBP of SHR elevated more than that of WKY with age. KMUP-1 (10 mg/kg) did not significantly decrease SBP of WKY. However, SBP of SHR by treating with KMUP-1 (10 mg/kg, 30 mg/kg) was significantly decreased as compared with SHR control. Moreover, eNOS, sGCα1 and PKG protein expression in SHR or WKY aorta by treating with KMUP-1 were significantly increased. In conclusion, KMUP-1 could active NO/cGMP pathway to improve SBP of SHR, suggesting that KMUP-1 could be a potential drug for hypertension.    Hypoxia exposure induced impairment in the structure and function of cardiopulmonary circulation. The pathological changes of cardiopulmonary arteries included endothelial injury, vessel remodeling, and contraction. It has been confirmed that hypoxia promoted downregulation of endothelial nitric oxide synthase (eNOS), upregulation of Rho kinase (ROCK) and vascular endothelial growth factor (VEGF) expression resulting in vascular contraction and remodeling to induce pulmonary arterial hypertension. Furthermore, activation of eNOS, soluble guanylyl cyclase (sGC), and protein kinase G (PKG) protein expression resulted in pulmonary arterial vasodilation and anti-remodeling. Previous studies have demonstrated that KMUP-1, a unique xanthine and piperazine derivative, activated the NO/sGC/cGMP pathway, and could lead to vascular relaxation. In the present study, the Wistar rats were subdivided into four groups：(1) Normoxia, (2) Hypoxia (10% O2) for 21 days, (3) Hypoxia (10% O2) + KMUP-1 (5 mg/kg/day) for 21 days, (4) Hypoxia (10% O2) + Sildenafil (5 mg/kg/day) for 21 days. After 21 days of hypoxia, we measured pulmonary arterial pressure to evaluate the development of pulmonary arterial hypertension. Through method of Hematoxylin-Eosin staining, we investigated wall thickness of pulmonary artery and right ventricular hypertrophy. Moreover, molecular mechanism was analyzed by Western blotting and immunohistochemistry.Our findings indicated that hypoxia could increase pulmonary arterial pressure, wall thickness ratio of pulmonary artery, and right ventricular hypertrophy as well as downregulate eNOS, sGCα1 and PKG protein expression whereas upregulate ROCK II and VEGF protein expression in molecular mechanism. However, the above effects could be reversed by treating with KMUP-1 or Sildenafil. In conclusion, our study confirmed that KMUP-1 is involved in the expression of eNOS/sGCα1/PKG signaling pathway resulting in vessel relaxation and may be useful for the improvement of hypoxia-induced pulmonary arterial hypertension in the future.

Lo scopo principale della tesi è valutare l’effetto del Vascular Endothelial Growth Factor (VEGF) e di alcune sostante e/o farmaci, che interagiscono sulla via di segnale cellulare da esso attivato (ossido nitrico dipendente), sulla funzione vascolare e in particolare sull’endotelio, sul microcircolo e sull’elasticità arteriosa. Inoltre intendiamo esplorare l’eventuale ruolo del VEGF nello sviluppo di disfunzione endoteliale, danno del microcircolo o dei grossi vasi potenzialmente implicati nell’insorgenza dell’ipertensione arteriosa. La tesi è stata suddivisa in 3 studi:1) scopo del primo studio: è dunque valutare il ruolo di alcuni componenti (licopene e TCMPs) contenuti nel frutto del pomodoro sulle cellule endoteliali. L’obiettivo primario del presente studio è valutare in cellule HUVEC i potenziali effetti di queste due componenti del pomodoro, in particolare considerare i loro effetti sulla sintesi di NO da cui dipende sia la funzione endoteliale che l’angiogenesi.Materiali e metodi. HUVECs incubate con licopene, TCMPs ed altre sostanze note quali VEGF e L-NAME sono state osservate al microscopio confocale valutando l’NO in termini d’intensità di fluorescenza. Risultati. Il licopene ha mostrato di modulare positivamente la produzione di NO intracellulare, mentre le TCMPs hanno mostrato un effetto inibitorio sia da sole che quando associate a stimolo con VEGF.Conclusioni. Lo studio evidenzia che i componenti del pomodoro hanno proprietà biologiche importanti, il licopene preserverebbe la funzione endoteliale mentre le TCMPs attenuerebbero una tappa critica dell’angiogenesi.2)copo della tesi era valutare l’effetto sulla funzione vascolare della salsa di pomodoro (80 grammi al giorno per sette giorni) confrontata con una dieta priva di pomodoro in volontari sani prima e dopo il consumo di un pasto ricco di grassi accompagnato o meno da ulteriori 80 grammi di salsa di pomodoro. Lo studio presenta un disegno a cross-over con un periodo di wash out di almeno 4 settimane tra le due fasi. I test vascolari a cui abbiamo sottoposto i pazienti sono stati: (i) la funzione endoteliale mediata da flusso (FMD) mediante metodica ecografica; (ii) lo “stiffness index” (SI) ed il reflection index (RI) mediante tecnica fortopletismografica; (iii) la distensibilità e la compliance carotidee mediante un sistema ecografico. Abbiamo incluso 19 maschi sani di età compresa tra 21 e 32 anni. Tutte le misure vascolari effettuate al basale nella prima giornata di studio non sono risultate significativamente diverse nei soggetti a seconda che avessero assunto o meno il pomodoro nella settimana precedente. Dopo il pasto grasso invece tutti i soggetti indipendentemente dall’assunzione o meno del pomodoro hanno mostrato una riduzione del RI (61,95 ± 9,18 % rispetto a 73,45 ± 10,05 % nei soggetti che avevano assunto il pomodoro; 64,83 ± 9,70 % rispetto a 70,73 ± 10,19 % nei soggetti che non avevano assunto pomodoro; P<0.001), indice di relativa vasodilatazione. Inoltre, solo i soggetti che avevano assunto pomodoro hanno mostrato rispetto al basale un incremento del diametro dell’arteria brachiale (4,25 ± 0,45 mm rispetto a 4,08 ± 0,39 mm, P<0.05), una riduzione della pressione diastolica (69,79 ± 7,28 mmHg rispetto a 73,07 ± 6,63 mmHg, P<0.05) ed un incremento della frequenza cardiaca (65,21 ± 8,41 bpm rispetto a 61,68 ± 9,73 bpm, P<0.05) 120 minuti dopo il pasto. Invece, i soggetti che non avevano assunto pomodoro hanno mostrato un incremento significativo dello SI 210 minuti dopo il pasto rispetto al basale (6,98 ± 1,24 m/sec rispetto a 6,58 ± 1,31 m/sec, P<0.05). Non abbiamo osservato modificazioni significative della FMD in tutti i punti dello studio. I nostri dati sono compatibili con un effetto del pomodoro in acuto, in aggiunta al pasto grasso, nel modificare alcuni indici emodinamici e in particolare di rigidità arteriosa. La nostra intenzione è di ampliare la casistica in modo da consolidare i risultati ottenuti, effettuare il dosaggio di metaboliti dell’ossido nitrico e del licopene per tentare di chiarire la fisiopatologia di questo fenomeno. 3) Lo scopo della tesi è di valutare in soggetti con carcinoma renale metastatizzato, l’effetto di farmaci oncologici anti-angiogenetici sui valori di pressione cercando di valutare se l´andamento degli stessi sia associato alla disfunzione endoteliale, alla riduzione dell´elasticitá vasale e/o al danno microcircolatorio. Lo studio ha coinvolto 19 soggetti di età compresa tra 59 e 77 anni, seguiti per un periodo di 3 mesi. Gli incontri si sono svolti in 3 tempi: il giorno di inizio della terapia (T0), a un mese (T1) e a tre mesi (T2) dal primo incontro. I test a cui abbiamo sottoposto i soggetti ad ogni visita sono stati: misurazione della pressione arteriosa con apparecchio elettronico oscillometrico (3 misurazioni a distanza di 5 minuti con il paziente sdraiato), misurazione della funzione endoteliale tramite la tecnica ecografica della vasodilatazione mediata da flusso (FMD: flow mediated dilatation), misurazione della distensibilità carotidea tramite ecografia dei tronchi sovraortici, studio ecocardiografico, capillaroscopia periungueale e raccolta delle urine. L’analisi dei dati ha mostrato un aumento della pressione arteriosa difforme nei pazienti: già dopo il primo mese di terapia anti-angiogenetica, nove pazienti hanno fatto registrare un incremento significativo dei valori di pressione (sia PAS che PAD) per cui è stato necessario incrementare/introdurre la terapia antipertensiva.La concentrazione di nitrati urinari, indice della produzione endogena di ossido nitrico, è risultata ridotta al basale nei sei pazienti con peggioramento pressorio rispetto ai pazienti che si sono mantenuti stabili . Ad un mese i valori di distensibilitá carotidea (DC) erano inferiori nei pazienti con peggioramento dei valori pressori rispetto ai pazienti stabili. Non abbiamo osservato modificazioni significative degli altri parametri emodinamici analizzati nei due gruppi né a 1 mese né a tre mesi. Abbiamo altresí osservato una correlazione inversa tra incremento dei valori di PAS (∆-PAS) e la riduzione dei valori di distensibilitá carotidea (∆-DC) ad un mese (r=-0,52; p<0,05). All’indagine capillascopica basale nessun soggetto presentava alterazioni capillariche senza apparente relazione con le modifiche dei valori pressori. Alla Tomografia Computerizzata (TC) a 6 mesi, 7 soggetti presentavano un quadro di progressione di malattia non correlata ai parametri vascolari. I nostri dati sono compatibili con un effetto dei farmaci anti-angiogenetici nel modificare la pressione arteriosa in pazienti “sensibili”. I dati raccolti suggeriscono un possibile ruolo dell´ossido nitrico o di altri fattori vasoattivi nelle modifiche della pressione arteriosa.
Aims of the study: evaluating the Vascular Endhitelial Growth Factor (VEGF) effect on systemic blood preassure and machanisms of regulation oxid nitric induced. 3 studies were been conducted:1) Aims of the first study: evaluating in vitro role of VEGF and lycopene, present in tomato fruit, on endothelial cells, using Human umbilical vein endothelial cells (HUVECs).Materials and methods: HUVECs were been incubated with lycopene (2μM), VEGF and L-NAME were observed by confocal microscopy the NO production in terms of fluorescence intensity (DAF) have been evaluated. Results: the DAF was higher in HUVECS incubated with lycopene (381,1 ± 126,99, p < 0,05 , n = 24 ) compared with control (292,6 ± 107,24 , n = 24); when cells were incubated with VEGF (10ng/ml) the intensity of fluorescence significantly increased (449,7 ± 115,64 p <0,05 , n=8). The supernatant of HUVECs incubated with lycopene showed the highest amounts of nitrate–nitrit. Conclusions: The study shows that the main component of tomato has important biological properties such as preservere endothelial function. Lycopene has been shown to positively modulate the production of intracellular NO.2) Aims of second study: testing whether a 7-day period of tomato paste supplementation can improve some haemodynamic parameters in healthy volunteers (HV) before and after a standardized fat meal.Methods and results: We enrolled 19 male HV in a randomized, single-blind (operator), crossover design. HV maintained a diet poor in vegetables during the study periods, starting a week before randomization. They were randomized either to a supplementation arm (70 g tomato paste per day) for 7 days or to a control arm (no added tomato paste) with a two-week washout periods between the different periods. Flow-Mediated Dilatation (FMD) and Carotid Distendibility (CD) by ultrasounds, Stiffness Index (SI), Reflection Index (RI) by photopletismography and blood pressure (BP), were measured as an estimate of vascular function before and after (2 and 3.5 hours) the fat meal. In the direct comparison between the 2 arms, only the difference in SI was increased in the without-tomato-arm as compared to the tomato-arm both at 2 and 3.5h points (Δ-mean [95%CI]: +0.46m/sec [0.01/0.93] m/sec, +0.55 [0.03/1.07m/sec], P<0.05). After the fat meal, in both arms, HV showed a marked reduction in RI at 2h (-10.7%[-6.7/-14.7%] with tomato paste; -7.2%[-3.0/-11.4%] without tomato paste; P<0.01). Interestingly, only in the tomato-arm, some haemodynamic changes were detectable at 2h with respect to baseline: in particular an increase in brachial artery diameter (+0.20mm[0.06/0.33mm], P<0.01), a reduction in diastolic BP (-2.4 mmHg[0.1/4.7 mmHg], P<0.05) and an increase in heart rate (+3.9bpm [1.4/6.4bpm], P<0.01). The same parameters were not significantly changed in the without-tomato-arm even if they resulted not significantly different between the two arms. The nitrites were higher il tomato group vs placebo one (85, 7 ± 42,2 vs 122,5 ± 83,4 p= 0,05)Conclusion: Tomato supplementation modifies some haemodynamic parameters triggered by a high fat diet suggesting a possible beneficial effect in people assuming a diet rich in tomato.3) Aims of the third study: evaluating the effect of antiangiogenitic drugs (antiVEGF/VEGFR) used in first line therapy in clear cellular carcinoma (CCR) on BP incidence, endothelial function, arterial rigidity and microvascular enviroment. Methods and results: We enrolled 19 hypertensive controlled/normotensive patients candidated to use antiangiogionetic drugs. Vascular test (flow mediated dilatation, carotid distensibility, capillaroscopy and BP) were measured at baseline (time 0 or T0), after 1 month of therapy (Time 1 or T1) and after 3 months of therapy (Time 2 or T2). We demonstrated an increase of BP in 47% of patients at time T1. We divided the population in two groups (patients with no preassure increase at T1 and patients with pressure increase at T1). At baseline population present some differences in particular levels of preassure (PAS 141,5±14,2 vs 123,1 ±11,9 p=0,008 e PAD 87,4±8,6 vs 77,7±8,0; p= 0,002), nitrates (no BP T1 92,7±46 vs BP T1 125±92 uM/mmol) and PLTs (no BP T1 218±56,8 and BP T1442±273,5; p =0,016). We documented a linear correlation betwen preassure increase and riduction in carotid distensibility at T1 (r=-0,52; p<0,05). The capillaroscopy was modified in 53% of patients after 1 month of therapy but with no significant differences in the two groups. Conclusion: the antiVGF therapy in our population determined an increase in BP and a modification in vassels structure tested with capillaroscopy. Although there were no correlations between preassure and capillary modifications. All those mechanisms can explain the important role of VEGF in blood preassure control. No direct correlation was identified between vascular caratheristics and cancer evolution.

The chapter begins by discussing key clinical skills, namely fundus fluorescein angiography, abnormal fluorescein angiography, indocyanine green angiography, and electrophysiology. The following areas of clinical knowledge are then discussed: diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, retinal artery occlusions, age-related macular degeneration, intravitreal anti-VEGF injections, central serous chorioretinopathy, retinal vascular anomalies, retinal dystrophies, and choroidal dystrophies. The chapter concludes with eight case-based discussions, on gradual visual loss, central visual loss, visual loss in a hypertensive patient, sudden, painless visual loss, diabetic retinopathy, difficult night vision, visual loss in child, and macular lesion.

This chapter starts off with a discussion of fundus fluorescein angiography and the causes of abnormal fluorescein angiography. It then discusses indocyanine green angiography, including the main indications for this technique. It goes on to cover fundus autofluorescence imaging and electrophysiology. It also includes clinical knowledge areas of diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, retinal artery occlusions, age-related macular degeneration, central serous chorioretinopathy, retinal vascular anomalies, inherited retinal disorders, macular dystrophies, and choroidal dystrophies. It also discusses a number of important clinical trial studies and contains a section on the use of intravitreal injections of agents against vascular endothelial growth factor (known as VEGF).

Although Na+ homeostasis in vivo is essential for mammals, it is known that excessive salt (NaCl) intake has played a major role in the development of hypertension. In vivo, there is a hormonal system, the renin-angiotensin-aldosterone system (RAAS), that specializes in regulating Na+ retention, especially the amount of Na+ in plasma. Na+ homeostasis in vivo has been achieved mainly by the RAAS, through regulation of vascular tonus (blood pressure) and Na+ handling in the kidney (Na+ diuresis). Recent studies have revealed a third mechanism of Na+ homeostasis in vivo: regulation of interstitial Na+ levels in tissues, such as subcutaneous tissues, by tissue macrophage immunity. In the pathogenesis of salt-sensitive hypertension, Recent research have been revealed that three molecular axes (Ang II - Rho/NOX-eNOS system, Aldosterone-rac1 -ENaC system, and tissue Na+ − TonEBP in macrophage -VEGF-c) are significantly involved in maintaining Na+ homeostasis in salt induced hypertension. Furthermore, the mechanism by which salt causes hypertension via the immune system (intestinal, local mucosal, and tissue immunity) has also been reported. In this article, we would like to propose that three molecular dysfunctions are involved in the development of salt-sensitive hypertension through three immunological mechanisms in the maintenance of Na+ homeostasis. Next, I would like to explain the importance of gut-RAAS and abnormality of intestinal microflora (dysbiosis) in salt-sensitive hypertension. It has been known that the metabolites (e.g., short-chain fatty acid neural amino) produced by microflora are deeply involved in central (CNS) and sympathetic nervous system (SNS) activity. In addition, we would like to explain of the importance of brain-RAAS and cerebral inflammation in salt-sensitive hypertension. Moreover, recent research have revealed that the detection-mechanism in the brain for Na+ concentration([Na+]) in vivo and in the tongue for [Na+] in diet. These finding suggests that excessive salt intake may cause brain dysfunction, most delicate organ, before the onset of salt sensitive hypertension, and may also destroy brain structure after the onset of salt sensitive hypertension. Thus, we would like to insist that excessive salt intake might not only induce hypertension, but also be toxic especially for brain. Finally, we would like to explain that The DASH diet (Dietary Approaches to Stop Hypertension) is one of the universal diets for adult human, not only by reducing salt, but also by reducing metabolic stress and improving of dysbiosis.

Diabetic retinopathy and diabetic foot ulcer are the most frequent, but also the most disabling complications of diabetes mellitus, with a sinister impact on patients’ quality of life. Microvascular changes related to the deleterious effect of chronic hyperglycemia play an important role in the pathophysiology of both clinical entities by multiple molecular pathways. Vision-threating diabetic retinopathy may be treated by laser photocoagulation, anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery. Diabetic foot lesions are best treated by revascularization if needed, off-loading, infection control and therapeutic adjuncts (e.g. special dressings). Treatment should ideally be offered by a multidisciplinary expert team. Prevention and early detection, along with adequate control of glucose, lipids and arterial hypertension are of paramount importance to avoid and mitigate these fearful complications.

Abstract This chapter begins with a discussion of fundus fluorescein angiography and the causes of abnormal fluorescein angiography. It then discusses indocyanine green angiography, including the main indications for this technique. It goes on to cover fundus autofluorescence imaging and electrophysiology. It also includes clinical knowledge areas of diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, retinal artery occlusions, age-related macular degeneration, central serous chorioretinopathy, retinal vascular anomalies, inherited retinal disorders, macular dystrophies, and choroidal dystrophies. It also discusses a number of important clinical trial studies and contains a section on the use of intravitreal injections of agents against vascular endothelial growth factor (known as VEGF).

Pulmonary arterial hypertension (PAH) is the most severe form of pulmonary hypertension due to its rapid progression to right ventricular (RV) failure. Until the recent combination of chronic hypoxia with VEGF receptor blockage by SU5416 [1], there was no mouse model for severe PAH. This new model (HySu) recapitulates hallmarks of human PAH, especially distal arteriolar neointima formation and obliteration [1]. However, the changes in RV function in this model have not been examined. Here we investigate the hypothesis that the HySu mouse model mimics the progression of RV dysfunction found in PAH clinically from compensatory to maladaptive RV remodeling.

Pulmonary artery hypertension (PAH) is a female dominant, fatal disease characterized by progressive increase of pulmonary vascular resistance and loss of compliance. The role of estrogen in these pulmonary vascular changes with PAH progression remains unclear. Our objective was to study the effects of estrogen on pulmonary arterial (PA) remodeling in a mouse model of progressive PAH, created via a combination of a VEGF inhibitor Sugen and chronic hypoxia (SuHx). To quantify PA hemodynamics, we measured in vivo pressure and flow simultaneously in live mice in order to obtain pulmonary vascular impedance, a comprehensive measure of RV afterload. Our results demonstrate that estrogen modifies the relationship between PA resistance and compliance by attenuating PA stiffening, which provides insight into sex differences in PAH progression.

Introduction: Efforts are going on for development of new drugs for epithelial ovarian cancer (EOC). We assessed safety profile of bevacizumab, a VEGF receptor blocking antibody in treatment of EOC. Methods: We assigned women with EOC to carboplatin (area under curve, 5 or 6) and paclitaxel (175 mg/square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (15 mg/kilogram body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 30 additional cycles. Primary outcome measures was safety profile of bevacizumab and secondary outcome was to see progression free survival (PFS). Results: Out of 30 patients, 10 were in Bevacizuma arm (Arm A) and 20 in conventional chemotherapy arm (Arm B). Haematological toxicity, GI perforation and proteinuria was similar in both. Other toxicities e.g. bleeding complication (p = 0.002) and hypertension (p = 0.04) was more in Arm A. PFS was similar in both arms; 24 months in Arm A and 22 months in Arm B (p = 0.565). 4 (40%) patients in arm A discontinued treatment, two (20%) because of disease progression after PFS of 9 and 6 months, two because of development of toxicity considered to be due to bevacizumab; of which one developed jejenal perforation and disease progression after PFS of 6 months and 1 because of development of persistent proteinuria of grade 3 after 18 months. Conclusion: Bevacizumab therapy does not improve PFS in EOC but increases toxicity spectrum of chemotherapy.