Добірка наукової літератури з теми "Vegfc/vegfr"

ABSTRACT Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3 −/− embryos, the Vegfc −/−; Vegfd −/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3 −/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3 neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc +/− mice in the K14-VEGF-D; Vegfc +/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.

e22147 Background: In tumor angiogenesis there is a complex interplay between endothelial, stromal and tumor cells. Some key regulators of this process are the members of the vascular endothelial growth factor (VEGF) family of ligands and receptors and the neuropilins (NRP). This study analyzes the correlations between the expression of these angiogenic factors in tumor cells and tumor stroma, and their prognostic role in tissue samples from resected non-small cell lung cancer (NSCLC) patients. Methods: Representative tumor and stroma areas from FFPE tissue samples of 125 early-stage NSCLC patients were carefully micro-dissected. RNA isolated from the samples was retrotranscripted and preamplified. RTqPCR was performed using hydrolysis probes (TaqMan, Applied Biosystems) and relative quantification was calculated using GAPDH and CDKN1B as endogenous controls. Results were normalized against a human cDNA (Clontech) as a reference. All statistical analyses were considered significant at p<0.05. Results: Paired Wilcoxon test revealed differences between tumor and stroma gene expression for VEGFB (p<0.0001), VEGFC (p<0.0001), VEGFR-1 (p<0.0001), VEGFR-2 (p=0.020), VEGFR-3 (p< 0.0001), NRP-1 (p=0.001) and NRP-2 (p< 0.0001). Survival analyses showed that those patients with higher levels of the Ratio Stromal-VEGFA/ Tumoral-VEGFR-2 had worse time to progression (TTP) (median 26.23 months vs NR, p=0.013) and overall survival (OS) (median 29.50 months vs NR, p=0.001). Similarly, those patients with higher levels of the Ratio Stromal-VEGFC/Tumoral-VEGFR-3 had worse TTP (median 23.30 vs 70.53 months, p=0.015) and OS (median 37.20 months vs NR, p=0.023). Conclusions: Our results show significant differences in the expression of VEGF family members between tumor and stromal cells. This may indicate the importance of the tumor-stroma interaction when trying to understand the angiogenic process. Furthermore, the combination of the ligands expression in stroma and their receptors in tumor may have a prognostic value in NSCLC patients. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII.

In cancer, the lymphatic system is hijacked by tumor cells that escape from primary tumor and metastasize to the sentinel lymph nodes. Tumor lymphangiogenesis is stimulated by the vascular endothelial growth factors-C (VEGFC) after binding to its receptor VEGFR-3. However, how VEGFC cooperates with other molecules to promote lymphatics growth has not been fully determined. We showed that lymphangiogenesis developed in tumoral lesions and in surrounding adipose tissue (AT). Interestingly, lymphatic vessel density correlated with an increase in circulating free fatty acids (FFA) in the lymph from tumor-bearing mice. We showed that adipocyte-released FFA are uploaded by lymphatic endothelial cells (LEC) to stimulate their sprouting. Lipidomic analysis identified the monounsaturated oleic acid (OA) as the major circulating FFA in the lymph in a tumoral context. OA transporters FATP-3, -6 and CD36 were only upregulated on LEC in the presence of VEGFC showing a collaborative effect of these molecules. OA stimulates fatty acid β-oxidation in LECs, leading to increased AT lymphangiogenesis. Our results provide new insights on the dialogue between tumors and adipocytes via the lymphatic system and identify a key role for adipocyte-derived FFA in the promotion of lymphangiogenesis, revealing novel therapeutic opportunities for inhibitors of lymphangiogenesis in cancer.

The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.

e16085 Background: Clear cell renal cell carcinomas (ccRCC) are hypervascular tumors that respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. They can be divided into 4 mRNA-expression based subgroups (ccrcc 1-4) with different outcomes on sunitinib. We hypothesized that the expression of proangiogenic genes is predictive for response to sunitinib. Methods: Retrospective series of metastatic ccRCC-patients treated with sunitinib as first line targeted therapy (n = 104). We studied expression of genes involved in angiogenesis and the immune-suppressive microenvironment (qRT-PCR) and mutational status of Von Hippel Lindau and Polybromo (PBRM) 1 (sequencing) on primary tumor samples. Outcome parameters were response rate (Response Evaluation Criteria in Solid Tumors), progression free survival (PFS) and overall survival (OS). Gene expression levels were tested in multivariate analysis (MV) against the IMDC risk criteria, presence of bone metastases and sarcomatoid dedifferentiation ≥25%. Results: Expression of Hypoxia Inducible Factor (HIF) 2A, Platelet Derived Growth Factor Receptor B, VEGFC, VEGFR1 and VEGFR2 was significantly correlated with PFS on MV and expression of HIF1A, HIF2A and VEGFR2 with OS. VEGFR2-expression was also correlated with partial response (p = 0.03) and anti-correlated with early progressive disease (p = 0.008). HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3-expression was higher in ccrcc2-tumors compared to others. Expression of genes involved in angiogenesis and in the immune-suppressive microenvironment was not directly correlated nor anti-correlated. In tumors with a bi-allelic PBRM1-inactivation, HIF2A, VEGFA, VEGFR1 and VEGFR2-expression were higher compared to tumors with 1 or 2 functional PBRM1-alleles. This did not translate in different outcome on sunitinib. Conclusions: Tumoral expression of genes involved in the HIF-VEGF-VEGFR proangiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in metastatic ccRCC. Expression of these genes was high in the molecular ccrcc2-subgroup, known to be sensitive to sunitinib. These findings could be used for patient selection in future clinical trials.

Abstract Introduction: Iron deficiency (ID) is one of the recognized causes of reactive thrombocytosis in children. Factors that are commonly associated with megakaryopoiesis such as thrombopoietin (TPO), interleukin 6 (IL-6) and IL-11 are not altered in patients with iron deficiency and thrombocytosis suggesting the role of alternate mechanisms in controlling this process. We have previously shown using an ID rat model that ID increased the number of megakaryocytes in the bone marrow. We have also shown an increase in VEGFR (FLT1) and CXCR4 staining in bone marrow slides of ID rats. This data suggests that angiogenesis plays a vital role in the development of reactive thrombocytosis in response to ID. In this report, we have expanded our study to identify specific angiogenic signaling molecules associated with ID and used functional assays to validate it. Methods: For this study, we used the megakaryoblast cell line MEG-01 as an in vitro model of megakaryopoiesis. MEG-01 cells were adapted to grow in chemically defined serum free medium containing iron (iron replete media). For iron deficiency, serum free iron free media was mixed with iron replete media at a 1% v/v concentration (iron deplete media). For our experiments, MEG-01 cells were grown in both iron replete and depleted media for 7 days. Cell viability was measured using the trypan blue exclusion assay. Messenger-RNA expression of iron-related markers (TFR1, TFR2, FLT1, FLT3, FTL, FTH1, TF, HMOX1 and HMOX2) and angiogenic markers (VEGFA, VEGFB, VEGFC, PDGF, ANGPTL1, ANGPTL2, FGF2) was studied using real time PCR. We performed functional validation of angiogenesis with an in vitro tube formation assay using human umbilical vein endothelial (HUVEC) cells. For statistical analysis of the data we performed the t test using graph pad prism software and we considered p<0.05 as statistically significant. Results: In low iron conditions, MEG-01 cells showed a significant increase in FLT1 (4 fold) and FLT3 (3 fold) expression using real time PCR (p<0.001). Iron deficiency also induced a 2 fold increase in the mRNA expression of angiogenic molecules VEGFB, VEGFC, FGF2 and PDGFA (p<0.001). Using the tube formation assay, we also show that conditioned media collected from iron deficient MEG-01 cells induced increased vessel formation in endothelial cells. Conclusion: In this study, we were able to validate our earlier in vivo findings on iron deficiency induced reactive thrombocytosis. We show that cells adapt to low iron conditions by upregulating FLT1, FLT3 and FTL. We also show that several markers in the angiogenesis pathway like VEGFB, VEGFC, FGF2 and PDGFA are upregulated in response to iron deficiency. We were also able to show that an increase in these angiogenic molecules induced increased vessel formation in endothelial cells. This report, along with our previous findings, points to the importance of the angiogenic pathway in reactive thrombocytosis induced by iron deficiency. Disclosures No relevant conflicts of interest to declare.

e15514 Background: Use of anti-angiogenesis drugs in pancreatic cancer has not yet resulted in significant clinical improvements and it is unknown if there are subsets of patients with pancreatic cancer that may benefit from this therapeutic approach. We have reported on a phase II trial of PTK/ZK (VEGFR inhibitor) in patients (n=65) who have failed or progressed on gemcitabine. The 6- month OS met the primary endpoint of 29 % and there were 2 partial responses. We investigated some of the plasma proteins relevant for angiogenesis in correlation with clinical outcomes on this trial. Methods: Plasma samples were obtained prior to and after 4 weeks of therapy with PTK/ZK, aliquoted and frozen until assayed. Patient plasma was assayed for: VEGFA, VEGFC, VEGFR1, VEGFR2, FGFb, PDGFBB, OPN, ANG2, IL-6, and sIL-6R (SearchLight, Pierce Biotechnology Multiplex ELISA and IL-6 and sIL-6R using R&D Systems).The Spearmen correlation was utilized to look for correlations and changes from baseline compared to post-treatment levels. The correlation of baseline levels with survival were analyzed using the Cox proportional hazard model. Results: Thirty eight paired patient samples were assayed. A significant correlation of baseline values was found between VEGF-C and VEGFR1 (p=0.0496), VEGF-C and VEGF (0.0092), PDGFB and ANG2 (p=0.0003), IL-6 and ANG2 (p=0.0089), and FGFb and OPN (p=0.0281). A correlation in post-treatment change was observed between VEGF-C and PDGFB (p=0.0008), FGFb and OPN (p=0.0374), PDGFB and ANG2 (p=0.0005), IL-6 and ANG-2 (p=0.0464), and VEGF and IL-6 (p=0.0546). Lower baseline IL-6 levels correlated with longer survival (p=0.0227). A post-treatment decrease in plasma IL-6 levels was significantly associated with improvement in survival (p=0.0457). IL-6 mediates multiple effects including angiogenic and pro-survival signaling and has been proposed as a potential prognostic factor in different malignancies. Conclusions: Of all angiogenesis markers analyzed only a post-treatment decrease in plasma IL-6 correlated with improved survival on study. IL-6 warrants further investigation as a potential marker of sensitivity to anti-angiogenesis therapy, especially in patients with pancreatic cancer. Supported by: 1P50 CA95060; 1PO1CA109552–01A1 [Table: see text]

Abstract Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for proliferation and survival. In the lymphoid follicle, FL cells are surrounded by follicular dendrytic cells (FDCs) that function as antigen presenting cells delivering survival and proliferation signaling. FDCs together with macrophages are associated to poor FL survival. Our aim was to uncover the signaling pathways underlying FL-FDC crosstalk and its validation as new targets for therapy using specific inhibitors. Global gene expression profiling of FL-FDC co-cultures yield a marked modulation of FL transcriptome by FDCs. The Principal Component Analysis (PCA) showed that HK-cocultured FL cells clustered together,independently of the patient origin. Then, pathways assignmentwas performed by DAVID and GSEA softwares, both of themuncovering an overrepresentation on genes related toangiogenesis. In the DAVID analysis, we found significant(False Discovery Rate (FDR)<5%,) angiogenesis–related GOterms such as, blood vessel development, blood vessel morphogenesis, VEGFR signaling pathway, sprouting angiogenesis, positive regulation of angiogenesis, patterning of blood vessels among others. In the GSEA analysis, our dataset was interrogated for enrichment of genesets belonging to C2 data base together with custom-derived ones. In accordance with DAVID results, genesets related to angiogenesis were enriched (FDR< 5%) in HK-cocultured FLcells, such as HumanAngiogenesis, Weston_VEGFA_targtes, PID_VEGFR1_2 and PID_lymphangiogenesis. As PI3K pathway is known to play a determinant role in angiogenesis, we explored if NVP-BKM120, a pan-PI3K inhibitor in clinical trials for solid tumors, could interfere with this signaling. First, by using Taqman Angiogenesis Array®containing 94 probes against genes related to angiogenesis, we analyzed if the modulation of genes in FL cells cocultured with HK could be inhibited by NVP-BKM120. Effectively, we found a group of genes that were positively regulated by HK and inhibited by NVP-BKM120, among them ANGPT1, CXCL12, EPHB2, VEGFA, VEGFC, ADAMST1, NRP1, NRP2, HSPG2,COL4A1, PDGFRA and PDGFRB. In addition, by ELISA analysis of cell culture supernatants, we found that NVP-BKM120 reduced VEGFA and VEGFC secretion of FL cells alone or co-cultured with HK. Then, we analyzed if this reduction of proangiogenic factors effectively reduced angiogenesis. To this aim we performed HUVEC tube formation assay with the supernatants of FL cells co-cultured or not with HK, in the presence or absence of the PI3K inhibitor. We demonstrated that, as expected, supernatants derived fromFL-HK-cocultures increased the number of tubes formed, and NVP-BKM120 reduced these numbers. Then, we investigated the impact of NVP-BKM120 treatment on FL cell signalling and proliferation. NVP-BKM120 efficiently blocks both constitutive activation of PI3K/AKT pathway in FL cells and that derived from B-cell receptor stimulation or HK co-culture, reducing cell proliferation of FL cells and inducing apoptosis in a portion of FL cell lines and primary cells. NVP-BKM120 also impedes signaling and migration induced by the chemokine SDF1α. In vivo, NVP-BKM120 significantly (p<0.05) reduces tumor outgrowth in subcutaneous and systemic FL mouse models. We isolated RNA from mouse tumors and run TaqmanAngiogenesis array as before. NVP-BKM120 downmodulated the expresion of genes related to angiogenesis already found in vitro such a VEGFA, HSPGB2, NRP2 ,PDGFRA and PDGFRB, but also novel genes, including SERPINC1, FST,PDGFB, TGFB1, TNF, VEGFB, COL18A1, ANGPT4 and PECAM(CD31). In addition, the reduction on VEGFA and CD31 was also validated by IHC in these tumors. These results warrant further investigation of pan-PI3K inhibitors for FL therapy in the context of microenvironment survival signaling inhibition. Disclosures: Lopez-Guillermo: Roche: Membership on an entity’s Board of Directors or advisory committees.

Abstract Acute myeloid leukemia (AML) is a disease with a poor prognosis. At this moment conventional chemotherapy is the gold standard for the treatment of AML. It is demonstrated that AML cells express VEGFA and VEGFC as well as KDR (VEGFR2), the main receptor for downstream effects, resulting in an autocrine pathway for cell survival. The present study investigates the role of PTK787/ZK 222584, a potent inhibitor of VEGF receptor tyrosine kinases, upon leukemic cell death, and the possibility of an additional effect upon cell death achieved by a conventional chemotherapeutic drug Amsacrine. In 3 AML-cell lines and 33 pediatric AML patient samples we performed total cell kill assays to determine the percentage of cell death achieved by PTK787/ZK 222584 (5–100 μM) and/or Amsacrine (0.001–2 μg/ml). Both drugs induced AML cell death. The LC50 values (drug concentration needed to kill 50% of the leukemic cells) for HL-60, TF-1 and THP-1 were 27 μM, 49 μM and 24 μM respectively. An excellent survival was seen on a KDR-negative cell line demonstrating that the cell death induced by PTK787/ZK 222584 is not a toxic effect. The primary blasts were overall 5–10 times more sensitive to PTK787/ZK 222584 than the cell lines, with a median LC50 value of 5.1 μM. Patient samples with a LC50 value below the median did not differ from patients above the median regarding age, sex, FAB classification or WBC count. With a response surface analysis we investigated the additional effect of PTK787/ZK 222584 upon cell death achieved by Amsacrine; we estimated the concentration combinations resulting in the same cell survival. We could show that, in cell lines as well as in primary AML blasts, the concentration of Amsacrine can be lowered and replaced for a certain dose of the potentially less toxic VEGFR inhibitor to achieve the same percentage of leukemic cell death. This study shows that PTK787/ZK 222584 might have more clinical potential in AML when combined with chemotherapy, e.g. Amsacrine. In addition, it is known from literature that topoisomerase inhibitors, e.g. Amsacrine, can cause treatment related AMLs. Moreover, many survivors of childhood or adolescent cancer experience treatment related cardiovascular complications that can impair their quality of life years after treatment. Therefore, reduction of complications and long-term effects of chemotherapy is warranted and might be achieved by lowering dosages of Amsacrine and replace it by other drugs with a lower toxicity profile, such as PTK787/ZK 222584.

Le médulloblastome (MB) est la tumeur pédiatrique cérébrale la plus fréquente et la plus agressive. Malgré un traitement multimodal agressif, entraînant des effets secondaires importants, 30% des patients développent une résistance et rechutent suite à l'apparition de métastases dans les 5 ans. Les récidives ne peuvent être contrôlées par des traitements conventionnels (radio et chimiothérapie) ou ciblés (anti-angiogénique, anti-inflammatoire, anti-point de contrôle immunitaire). L'objectif de ma thèse est donc de découvrir de nouvelles cibles et stratégies thérapeutiques pertinentes pour ces patients au diagnostic ou après une rechute.Les MB sont des tumeurs très vascularisées. Le phénomène de résistance est, en partie, lié au développement de vaisseaux sanguins (angiogenèse) et lymphatiques (lymphangiogenèse) dans la tumeur, qui constituent les principales voies de dissémination métastatique. Le facteur de croissance des vaisseaux lymphatiques, le VEGFC, et ses récepteurs/co-récepteurs sont les acteurs majeurs de la lymphangiogenèse. Dans la première partie de ma thèse, j'ai montré que le VEGFC est inversement corrélé à la croissance et l'agressivité cellulaire du MB. En effet, le VEGFC diminue de manière autocrine la prolifération et la migration des cellules MB, ainsi que leur capacité à former des pseudo-vaisseaux in vitro. Les cellules résistantes à la radiothérapie présentent des niveaux élevés de VEGFC et perdent leur capacité à migrer et à former des pseudo-vaisseaux. L'irradiation réduit l'agressivité des cellules de MB par un processus dépendant du VEGFC. Les cellules surexprimant le VEGFC et les cellules résistantes à l'irradiation forment des tumeurs expérimentales plus petites chez la souris Nude. Le VEGC semble être un régulateur négatif de la croissance des MB. Ces résultats ouvrent la voie au développement de thérapies pro-VEGFC dans ces cancers.Dans la seconde partie de ma thèse, j'ai corrélé l'expression de la voie de signalisation pro-angiogénique et pro-inflammatoire ELR+CXCL/CXCR1-2 à une survie plus courte chez des patients atteints de MB. J'ai montré qu'un nouvel inhibiteur pharmacologique (C29) des récepteurs CXCR1-2 inhibe la prolifération, la migration dépendante de CXCL8/CXCR1/2, l'invasion et la formation de pseudo-vaisseaux par des cellules de MB sensibles ou résistantes à la radiothérapie. C29 réduit la croissance de MB expérimentaux dans un modèle de souris organotypique ex vivo et traverse la barrière hémato-encéphalique. Ainsi, le ciblage de CXCR1-2 représente une stratégie prometteuse pour le traitement des MB pédiatriques, en première ligne ou à la suite de rechutes.Mots-clés : médulloblastome pédiatrique, VEGFC/VEGFR, CXCR1-2, cytokines ELR+CXCL, thérapie ciblée, lymphangiogenèse, angiogenèse
Medulloblastoma (MB) is the most common and aggressive pediatric brain tumor. Despite aggressive multimodal treatment, resulting in significant side effects, 30% of patients develop resistance and relapse following the appearance of metastases within 5 years. Recurrences cannot be controlled by conventional (radio- and chemotherapy) or targeted (anti-angiogenic, anti-inflammatory, anti-immune checkpoint) treatments. The objective of my thesis is therefore to discover new targets and relevant therapeutic strategies for these patients at diagnosis or after a relapse.MBs are highly vascularized tumors. The phenomenon of resistance is, in part, linked to the development of blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels in the tumor, which constitute the main routes of metastatic dissemination. The lymphatic growth factor, VEGFC, and its receptors/co-receptors are the major players in lymphangiogenesis. In the first part of my thesis, I showed that VEGFC is inversely correlated to MB cell growth and aggressiveness. Indeed, VEGFC decreases the proliferation and migration of MB cells, as well as their ability to form pseudo-vessels in vitro, by an autocrine signalization. Cells resistant to radiotherapy show elevated levels of VEGFC and lose their ability to migrate and form pseudo-vessels. Irradiation reduces the aggressiveness of MB cells by a VEGFC-dependent process. VEGFC-overexpressing cells and radiation-resistant cells form smaller experimental tumors in nude mice. Thus, VEGC appears to be a negative regulator of MB growth. These results pave the way for the development of pro-VEGFC therapies in these cancers.In the second part of my thesis, I correlated the expression of the ELR+CXCL/CXCR1-2 pro-angiogenic and pro-inflammatory signaling pathway to shorter survival in patients with MB. I showed that a novel pharmacological inhibitor (C29) of CXCR1-2 receptors inhibits proliferation, CXCL8/CXCR1-2-dependent migration, invasion and pseudo-vessel formation by susceptible or resistant MB cells to radiotherapy. C29 reduces the growth of experimental MBs in an ex vivo organotypic mouse model and crosses the blood-brain barrier. Thus, targeting CXCR1-2 represents a promising strategy for the treatment of pediatric MB, at first line or at relapse.Key words: pediatric medulloblastoma, VEGFC/VEGFR, CXCR1-2, ELR+CXCL cytokines, targeted therapy, lymphangiogenesis, angiogenesis

碩士
國立臺灣大學
動物學研究所
100
Lysophosphatic acid receptor 1 (Lpar1) has been suggested to have some roles in vascular development because of its high expression in endothelial cells (ECs). However, no significant defect in vascular development was observed in lpar1-knockout mice. We have previously demonstrated that knockdown of lpar1 causes craniofacial cartilage distortion and serious edema in zebrafish. Edema was resulted from the defect in lymphangiogenesis, so I intended to further analyze the expression and regulatory mechanism of Lpar1 in lymphangiogenesis during embryonic development. lpar1 was expressed in dorsal aorta where a lymphatic factor, vegfc, was also expressed. Knockdown of lpar1 caused narrowed space between dorsal aorta and posterior caudal vein. Real-time PCR analysis showed that vegfc but not another lymphatic factor lyve-1 like was reduced in lpar1 morphants. Inhibition of cyclooxygenase-2 (Cox2) caused similar defects in lymphangiogenesis as that in the lpar1 morpholino-injected embryos, but it was unable to be rescued by ectopic expression of cox2 at low dosage. From the results, I suggested that Lpar1 may regulate the expression of vegfc and affect the formation of lymphatic vessels, but its regulatory mechanism remains unclear.