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Results for “Endothelialization”

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At least 271 records · Page 15Linked to original sources

PubMed2005

Modulation of tumor endothelial cell marker 7 expression during endothelial cell capillary morphogenesis.

Angiogenesis, the process of new blood vessel formation from preexisting capillaries, is a multistep process. The principle cell type in this process is endothelial cells which are required to undergo proliferation, migration, differentiation, and coalescence into cord-like structures with a central lumen. However, the molecular and cellular mechanisms that regulate this process require further investigation. In this study, we have used the fibrin/fibrinogen-based three-dimensional culture to enrich for primary cultured mouse aortic endothelial cells, and to induce endothelial cell capillary morphogenesis. We found among all the cell surface markers examined that only TEM7 expression was up-regulated upon endothelial cells capillary morphogenesis. In addition, inhibition of capillary morphogenesis by serum stimulation completely blocked TEM7 expression. In contrast, stimulation of endothelial cell capillary morphogenesis with PMA enhanced TEM7 expression. Furthermore, incubation of endothelial cells with a recombinant extracellular domain of TEM7 blocked capillary morphogenesis in three-dimensional cultures. These results suggest that TEM7 is a novel protein whose cell surface expression is essential during endothelial cell capillary morphogenesis.

Animals↗

PubMed2006

Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function.

Previous studies have shown that heat stress possesses cardioprotection, which is related to the synthesis and release of calcitonin gene-related peptide (CGRP) via activation of capsaicin receptor (vanilloid receptor subtype 1, VR1) on the capsaicin-sensitive sensory neurons. The VR1 exists in human umbilical vein endothelial cells (HUVECs). Endothelial cells can synthesize CGRP and CGRP could protect against endothelial dysfunction induced by lysophosphatidylcholine (LPC) or oxidized low-density lipoprotein. In the present study, we explored whether the endothelial cell-derived CGRP is involved in the effect of heat stress on endothelial function in vivo and in vitro. Our results indicated that heat stress significantly increased the plasma concentration of CGRP, which was abolished by pretreatment with capsazepine, a VR1 antagonist. Immunohistochemistry and in situ hybridization showed that the endothelium of mesenteric artery and aorta expressed CGRP. And heat stress increased the expression of CGRP, which was also abolished by capsazepine. LPC attenuated the endothelium-dependent relaxation responses of aorta rings, which were improved by pretreatment with heat stress. In cultured HUVECs, the CGRP secretion was increased after heat stress. LPC increased the lactate dehydrogenase (LDH) activity in the cultured medium and decreased the cell viability, suggesting that LPC injured the HUVECs. However, pretreatment with heat stress attenuated the injurious effects of LPC on HUVECs. And this beneficial effect of heat stress on HUVECs was inhibited by capsazepine or CGRP(8-37), the CGRP receptor antagonist. The present results suggest that the endothelial cell-derived CGRP contributes to the protective effects of heat stress on endothelial function. Our study provides a potential mechanism to explain the protective effect of heat stress on cardiovascular system.

Animals↗

PubMed1999

Inhibition of platelet-activating factor, intercellular adhesion molecule 1 and platelet endothelial cell adhesion molecule 1 reduces experimental pancreatitis-associated gut endothelial barrier dysfunction.

BACKGROUND: Endothelial barrier dysfunction is a critical link in the development of tissue injury and organ dysfunction, via upregulation and exposure of adhesion molecules, intercellular signals and leucocyte-endothelial cell interactions. Inhibitors of inflammatory mediators and receptors have been suggested as a means of downregulating the cascade of both local and systemic inflammation. METHODS: The potential therapeutic inhibition of platelet-activating factor (PAF), intercellular adhesion molecule (ICAM) 1 and platelet endothelial cell adhesion molecule (PECAM) 1 was investigated in pancreatitis-associated gut endothelial dysfunction in rats, by treatment with a PAF antagonist (lexipafant, BB-882) and monoclonal antibodies against rat ICAM-1 (anti-ICAM1-Mb) and PECAM (anti-PECAMA1-Mb). Alterations in gut endothelial barrier dysfunction and leucocyte recruitment, and systemic levels of interleukins were evaluated. RESULTS: Plasma exudation measured by the albumin leakage index and tissue leucocyte recruitment in the distal small intestine and colon increased significantly 12 h after induction of pancreatitis and treatment with saline. These alterations were to varying degrees counteracted by treatment with lexipafant, anti-ICAM1-Mb or anti-PECAM1-Mb. Alterations in levels of interleukin (IL) 1 paralleled the changes in gut endothelial barrier dysfunction and leucocyte trapping. CONCLUSION: Treatment with lexipafant and monoclonal antibodies against ICAM-1 or PECAM-1 reduced the severity of pancreatitis-associated gut endothelial dysfunction, and decreased systemic concentrations of IL-1 and local leucocyte recruitment.

Animals↗

PubMed2004

Interaction between hex and GATA transcription factors in vascular endothelial cells inhibits flk-1/KDR-mediated vascular endothelial growth factor signaling.

Recent evidence supports a role for GATA transcription factors as important signal intermediates in differentiated endothelial cells. The goal of this study was to identify proteins that interact with endothelial-derived GATA transcription factors. Using yeast two-hybrid screening, we identified hematopoietically expressed homeobox (Hex) as a GATA-binding partner in endothelial cells. The physical association between Hex and GATA was confirmed with immunoprecipitation in cultured cells. Hex overexpression resulted in decreased flk-1/KDR expression, both at the level of the promoter and the endogenous gene, and attenuated vascular endothelial growth factor-mediated tube formation in primary endothelial cell cultures. In electrophoretic mobility shift assays, Hex inhibited the binding of GATA-2 to the flk-1/KDR 5'-untranslated region GATA motif. Finally, in RNase protection assays, transforming growth factor beta1, which has been previously shown to decrease flk-1 expression by interfering with GATA binding activity, was shown to increase Hex expression in endothelial cells. Taken together, the present study provides evidence for a novel association between Hex and GATA and suggests that transforming growth factor beta-mediated repression of flk-1/KDR and vascular endothelial growth factor signaling involves the inducible formation of inhibitory Hex-GATA complexes.

Cell Line↗

PubMedDate not supplied

Metallothionein 1 is a downstream target of vascular endothelial zinc finger 1 (VEZF1) in endothelial cells and participates in the regulation of angiogenesis.

Vascular endothelial zinc finger 1 (VEZF1) is a transcription factor that is expressed in endothelial cells and plays a requisite role in the regulation of angiogenesis. The authors' previous microarray analysis revealed that the down-regulation of VEZF1 gene resulted in the decrease of metallothionein 1 (MT1) gene in endothelial cells. Here the authors showed by Northern blotting that the down-regulation of VEZF1 decreased, whereas up-regulation of VEZF1 increased, the expression of MT1 in endothelial cells. Moreover, MT1 was expressed in endothelial cells at the site of angiogenesis in vivo. The authors therefore examined whether MT1 played any role in the regulation of angiogenesis. Down-regulation of MT1 in endothelial cells inhibited proliferation, migration, and network formation in vitro, as well as angiogenesis in vivo. Moreover, down-regulation of MT1 resulted in the cell cycle arrest at G1 phase. These results indicate that MT1 is a downstream target of VEZF1 in endothelial cells and is involved in the regulation of angiogenesis.

Animals↗

PubMed2006

Neisseria meningitidis infection of human endothelial cells interferes with leukocyte transmigration by preventing the formation of endothelial docking structures.

Neisseria meningitidis elicits the formation of membrane protrusions on vascular endothelial cells, enabling its internalization and transcytosis. We provide evidence that this process interferes with the transendothelial migration of leukocytes. Bacteria adhering to endothelial cells actively recruit ezrin, moesin, and ezrin binding adhesion molecules. These molecules no longer accumulate at sites of leukocyte-endothelial contact, preventing the formation of the endothelial docking structures required for proper leukocyte diapedesis. Overexpression of exogenous ezrin or moesin is sufficient to rescue the formation of docking structures on and leukocyte migration through infected endothelial monolayers. Inversely, expression of the dominant-negative NH(2)-terminal domain of ezrin markedly inhibits the formation of docking structures and leukocyte diapedesis through noninfected monolayers. Ezrin and moesin thus appear as pivotal endothelial proteins required for leukocyte diapedesis that are titrated away by N. meningitidis. These results highlight a novel strategy developed by a bacterial pathogen to hamper the host inflammatory response by interfering with leukocyte-endothelial cell interaction.

Cell Adhesion↗

PubMed2005

Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased morbidity and mortality attributable to accelerated atherosclerosis and cardiovascular events. OBJECTIVE: To determine the role played by endothelial progenitor cells (EPC) in the defence system against arteriosclerosis. METHODS: The number and function of EPC in 13 young patients with RA with low disease activity (DAS28 3.5 (0.3)) and 13 healthy control subjects was studied. Endothelial function was investigated by agonist-induced, endothelium dependent vasodilatation measured by the forearm blood flow technique. Migratory activity and adhesion of EPC to tumour necrosis factor alpha (TNFalpha) activated mature endothelial cells and components of the extracellular matrix were tested in vitro. Putative precursor populations (CD34(+), CD34(+)/CD133(+), and CD34(+)/KDR(+) haematopoietic stem cells) were measured by flow cytometric analysis. RESULTS: Acetylcholine-induced, endothelium dependent vasodilatation was reduced by about 50% in patients with RA, indicating endothelial dysfunction, whereas endothelium-independent vasodilatation in response to glyceryl trinitrate was at control level. Significantly reduced numbers of EPC were found in the patients compared with controls. Migratory activity of EPC was decreased in patients with RA. Adhesion to mature endothelial cells after activation with TNFalpha was enhanced only in controls. The adhesion to matrix proteins and the number of putative precursor cell lineages was comparable in both groups. CONCLUSION: Endothelial dysfunction in patients with RA with low grade inflammation is associated with a reduced number and partial dysfunction of EPC. Further studies are needed to explore whether interventions that potentially ameliorate the number and function of EPC also improve endothelial function in these patients.

Acetylcholine↗

PubMed2005

Presence of endothelial progenitor cells, distinct from mature endothelial cells, within human CD146+ blood cells.

CD146 is an adhesion molecule present on endothelial cells throughout the vascular tree. CD146 is also expressed by circulating endothelial cells (CECs) widely considered to be mature endothelial cells detached from injured vessels. The discovery of circulating endothelial progenitor cells (EPCs) originating from bone marrow prompted us to investigate whether CD146 circulating cells could also contains EPCs. We tested this hypothesis using an approach combining elimination of CECs by an adhesion step, followed by immunomagnetic sorting of remaining CD146+ cells from the non adherent fraction of cord blood mononuclear cells. When cultured under endothelial-promoting conditions, these cells differentiated as late outgrowth endothelial colonies: they grew as a cobblestone monolayer, were uniformly positive for endothelial markers and did not express leukocyte antigens. They highly proliferated and were expanded in long-term culture without alterations of their phenotypic and functional properties (Dil-ac-LDL uptake, wound repair, capillary-like network formation, and TNFalpha response). Moreover, these cells colonized a Matrigel plug in immunodeficient mice (NOD/SCID). Finally, using 4-color flow cytometry analysis of purified CD34+ cells, we clearly discriminated, CD146+ EPCs (CD146+ CD34+ CD45+ CD133+ or CD117+), and CD146+ CECs (CD146+ CD34+, CD45- CD133- or CD117-), both in cord and adult peripheral blood.The relative proportions of the two CD146+ subsets varied in patients with myocardial infarction as compared to healthy subjects. Our study establishes that, beside CECs, CD146+ circulating cells contain a subpopulation of EPCs with potential use in proangiogenic therapy. In addition, the dual measurement of CD146+ CECs and CD146+ EPCs offers a promising tool for monitoring vascular injury/regeneration processes in clinical situations.

Animals↗

PubMed2005

Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor.

BACKGROUND: Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis, which leads to progressive heart failure; however, the pathogenesis of DCM remains uncertain. METHODS AND RESULTS: Using the streptozotocin-induced diabetic rat model, we evaluated the natural course of DCM over a period of 1 year by serial echocardiography, Western blot analysis for vascular endothelial growth factor (VEGF), endothelial progenitor cell assays, myocardial blood flow measurements, and histopathologic analysis that included terminal dUTP nick end-labeling (TUNEL), capillary and cardiomyocyte density, and fibrosis area. Downregulation of myocardial VEGF expression preceded all other features of DCM and was followed by increased apoptosis of endothelial cells, decreased numbers of circulating endothelial progenitor cells, decreased capillary density, and impaired myocardial perfusion. Apoptosis and necrosis of cardiomyocytes ensued, along with fibrosis and progressive diastolic and then systolic dysfunction. To provide further evidence of the central role of VEGF in the pathophysiology of DCM, we replenished myocardial VEGF expression using naked DNA gene therapy via direct intramyocardial injection of plasmid DNA encoding VEGF (phVEGF165). VEGF-replenished rats showed increased capillary density, decreased endothelial cell and cardiomyocyte apoptosis, and in situ differentiation of bone marrow-derived endothelial progenitor cells into endothelial cells. These anatomic findings were accompanied by significant improvements in cardiac function. CONCLUSIONS: These findings suggest that downregulation of VEGF may compromise microvascular homeostasis in the myocardium and thereby play a central role in the pathogenesis of DCM.

Animals↗

PubMed2004

Transplantation of circulating endothelial progenitor cells restores endothelial function of denuded rabbit carotid arteries.

BACKGROUND AND PURPOSE: Circulating endothelial progenitor cells (EPCs) play an important role in repair of injured vascular endothelium and neovascularization. The present study was designed to determine the effect of EPCs transplantation on the regeneration of endothelium and recovery of endothelial function in denuded carotid arteries. METHODS: Isolated mononuclear cells from rabbit peripheral blood were cultured in endothelial growth medium for 7 days, yielding EPCs. A rabbit model of common carotid artery denudation by passage of a deflated balloon catheter was used to evaluate the effects of EPCs on endothelial regeneration and vasomotor function. Immediately after denudation, autologous EPCs (10(5) cells in 200 microL saline) or 200 microL saline alone (control) were administered into the lumen of injured artery. RESULTS: Four weeks after transplantation, fluorescence-labeled colonies of EPCs were found in the vessel wall. Local transplantation of EPCs as compared with saline administration accelerated endothelialization and significantly improved endothelium-dependent relaxation when assessed 4 weeks after denudation (n=4 to 5, P<0.05). Transplantation of EPCs did not affect vasomotor function of arterial smooth muscle cells. Protein array analysis of conditioned media obtained from cultured EPCs demonstrated the ability of these cells to produce and release a number of proangiogenic cytokines. CONCLUSIONS: We conclude that local delivery of cultured circulating EPCs into the lumen of denuded carotid arteries accelerates endothelialization and improves endothelial function. Paracrine effects of EPCs may contribute to regenerative properties of EPCs.

Animals↗

PubMed2001

Phenotypic characterization of human umbilical vein endothelial (ECV304) and urinary carcinoma (T24) cells: endothelial versus epithelial features.

ECV304 cells reported as originating from human umbilical vein endothelial cells by spontaneous transformation have been used as a model cell line for endothelia over the last decade. Recently, deoxyribonucleic acid fingerprinting revealed an identical genotype for ECV304 and T24 cells (urinary bladder carcinoma cell line). In order to resolve the apparent discrepancy between the identical genotype and the fact that ECV304 cells phenotypically show important endothelial characteristics, a comparative study was performed. Immortalized porcine brain microvascular endothelial cells/C1-2, and Madin Darby canine kidney cells were included as typical endothelial and epithelial cells, respectively. Various methods, such as confocal laser scanning microscopy. Western blot, and protein activity tests, were used to study the cell lines. ECV304 and T24 cells differ in criteria, such as growth behavior, cytoarchitecture, tight junction arrangement. transmembrane electrical resistance, and activity of gamma-glutamyltransferase. Several endothelial markers (von Willebrand factor, uptake of low-density lipoprotein, vimentin) could clearly be identified in ECV304, but not in T24 cells. Desmoglein and cytokeratin, both known as epithelial markers, were found in ECV304 as well as in T24 tells. However, differences were found for the two cell lines with respect to the type of cytokeratin: in ECV304 cells mainly cytokeratin 18 (45 kDa) is found, whereas in T24 cells cytokeratin 8 (52 kDa) is predominant. As we could demonstrate, the ECV304 cell line exposes many endothelial features which, in view of the scarcity of suitable endothelial cell lines, still make it an attractive in vitro model for endothelia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The expression of vascular endothelial platelet endothelial cell adhesion molecule-1 is not regulated by IFN-gamma treatment of C6 tumors in vivo.

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a glycoprotein that is constitutively expressed on the surface of endothelial cells, leukocytes, platelets, monocytes and neutrophils. It has been proposed that PECAM-1 plays a role in transendothelial leukocyte trafficking. In vitro studies have suggested that interferon-gamma (IFN-gamma) may regulate PECAM-1 expression on endothelial cells. We have investigated the in vivo regulatory role of mouse IFN-gamma (mIFN-gamma) on the expression of PECAM-1 on vascular endothelial cells during tumor angiogenesis. In situ retroviral gene transfer was used to deliver mIFN-gamma into established subcutaneous tumors in athymic (nu/nu) mice. The biological activity of mIFN-gamma expressed intratumorally, was verified by i) a macrophage and granulocyte (predominantly neutrophil) infiltrate observed within C6 tumors following mIFN-gamma treatment; ii) an up-regulation of major histocompatibility complex (MHC) class I and II expression on the surface of tumor cells following mIFN-gamma treatment. Indirect immunohistochemical localisation of PECAM-1 expression was performed on control and mIFN-gamma-treated C6 tumor sections. The intensity and distribution of PECAM-1 expression on vascular endothelial cells in mIFN-gamma-treated tumors was similar to control tumors. Immunohistochemical staining of PECAM-1 was compared to factor VIII-related antigen in serial tumor sections. No differences were observed between the vascular endothelial cells expressing PECAM-1 and factor VIII in serial sections of control and mIFN-gamma-treated tumors. Therefore, in this in vivo C6 tumor model, IFN-gamma does not alter PECAM-1 expression on tumor-associated vascular endothelial cells.

Animals↗

PubMed1995

Vascular endothelial growth factor causes endothelial proliferation after vascular injury.

Vascular endothelial growth factor was infused into rat carotid arteries for 3 minutes immediately after endothelial denudation by balloon injury. Endothelial proliferation was determined by immunohistochemical labelling of proliferating cell nuclear antigen using Häutchen preparations. The proliferation index, or number of proliferating cells/total cells, measured at 25.5 or 30 hours was markedly increased after infusion of vascular endothelial growth factor. In addition, the total number of proliferating cells increased with increasing doses up to 100 micrograms total dose per infusion. These data indicate that infusion of vascular endothelial growth factor increases endothelial cell proliferation after mechanical denudation injury of the vascular wall.

Animals↗

PubMed1997

Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: balance between growth and death signals.

A series of experiments was performed to determine whether vascular endothelial growth factor (VEGF), in addition to its endothelial cell specific mitogenic activity, can also protect endothelial cells from toxin-induced programmed cell death. Apoptosis was induced in endothelial cell culture with tumor necrosis factor-alpha (TNF-alpha). Simultaneous exposure of endothelial cells to VEGF resulted in a dose dependent inhibition of apoptosis when evaluated by: (1) direct counting of cells with morphologic features of apoptosis after acridine orange staining; (2) analysis of DNA fragmentation by (a) agarose gel electrophoresis and (b) fluorescence activated cell sorting (FACS); and (3) viability assays dependent upon mitochondrial function. Induction of fibronectin and beta 3 integrin expression in endothelial cells by VEGF suggests that altered adhesion molecule expression may explain this survival effect.

Animals↗

PubMed1996

Down-regulation of vascular endothelial growth factor in human colon carcinoma cell lines by antisense transfection decreases endothelial cell proliferation.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent paracrine angiogenic factor implicated in human colon cancer angiogenesis. This study determined whether regulation of VEGF expression by human colon cancer cell lines affects endothelial cell proliferation in an in vitro model of angiogenesis. METHODS: Human colon carcinoma cell lines were screened for VEGF mRNA expression. SW480 cells (low VEGF expresser) were transfected with the VEGF sense (VS) vector, and SW620 cells (high VEGF expresser) were transfected with the VEGF antisense (VAS) vector. Cells were transfected with the vector alone as control. Endothelial cells were grown in conditioned, serum-free medium produced from experimental cells, and proliferation was determined. RESULTS: SW480-VS transfectants exhibited a sixfold increase in VEGF secretion. SW620-VAS transfectants exhibited a 50% reduction in VEGF secretion. Endothelial cells grown in conditioned medium from SW480-VS cells exhibited a 1.5- to 2-fold increase in proliferation. Addition of conditioned medium from SW620-VAS cells resulted in a 25% to 50% decrease in endothelial cell proliferation. CONCLUSIONS: VEGF production by human colon cancer cells regulates endothelial cell proliferation. Antisense VEGF transfection can down-regulate VEGF secretion and biologic activity. Therapies to decrease VEGF expression may be a means of inhibiting angiogenesis in primary and metastatic colon cancer.

Alternative Splicing↗

PubMed2006

The scaffolding adapter Gab1 mediates vascular endothelial growth factor signaling and is required for endothelial cell migration and capillary formation.

Vascular endothelial growth factor (VEGF) is involved in the promotion of endothelial cell proliferation, migration, and capillary formation. These activities are mainly mediated by the VEGFR2 receptor tyrosine kinase that upon stimulation, promotes the activation of numerous proteins including phospholipase Cgamma (PLCgamma), phosphatidylinositol 3-kinase (PI3K), Akt, Src, and ERK1/2. However, the VEGFR2-proximal signaling events leading to the activation of these targets remain ill defined. We have identified the Gab1 adapter as a novel tyrosine-phosphorylated protein in VEGF-stimulated cells. In bovine aortic endothelial cells, Gab1 associates with VEGFR2, Grb2, PI3K, SHP2, Shc, and PLCgamma, and its overexpression enhances VEGF-dependent cell migration. Importantly, silencing of Gab1 using small interfering RNAs leads to the impaired activation of PLCgamma, ERK1/2, Src, and Akt; blocks VEGF-induced endothelial cell migration; and perturbs actin reorganization and capillary formation. In addition, co-expression of VEGFR2 with Gab1 mutants unable to bind SHP2 or PI3K in human embryonic kidney 293 cells and bovine aortic endothelial cells mimics the defects observed in Gab1-depleted cells. Our work thus identifies Gab1 as a novel critical regulatory component of endothelial cell migration and capillary formation and reveals its key role in the activation of VEGF-evoked signaling pathways required for angiogenesis.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Endostatin down-regulates soluble guanylate cyclase (sGC) in endothelial cells in vivo: influence of endostatin on vascular endothelial growth factor (VEGF) signaling.

Endostatin was suggested to be an antiangiogenic agent with the potential for clinical use in cancer therapy. Unfortunately, up to now no antiangiogenic effect was seen in clinical trials using this substance. The lack of response might be caused by an incomplete understanding of endostatin signaling. Endostatin is known to influence the vascular endothelial growth factor (VEGF) signaling pathway. It has been reported to bind to the VEGF receptor KDR directly and to decrease the phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 via the protein phosphatase 2A (PP2A). But so far no details of endostatin signaling with regard to NO downstream effectors have been revealed. In the present work the authors demonstrate that endostatin down-regulates the protein level of soluble guanylate cyclase (sGC) in endothelial cells of newly formed blood vessels in 5 day-old wounds (control: 62.5 +/- 33 vessels/mm2, endostatin: 9.2 +/- 3.2 vessels/mm2). This was confirmed in experiments with endothelial tubes of embryoid bodies and endothelial cells derived from embryonic stem cells (eESCs; control: 126 +/- 20, endostatin: 58 +/- 10). The decrease of sGC protein levels in response to endostatin was abolished after preincubation with the PP2A inhibitor okadaic acid. No alterations of sGC mRNA levels could be found under endostatin treatment in eESC. The authors conclude that endostatin affects VEGF signaling in endothelial cells by a post-transcriptional PP2A-dependent down-regulation of sGC protein levels.

Angiogenesis Inhibitors↗

PubMed1998

Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis.

FGF-2 and VEGF are potent angiogenesis inducers in vivo and in vitro. Here we show that FGF-2 induces VEGF expression in vascular endothelial cells through autocrine and paracrine mechanisms. Addition of recombinant FGF-2 to cultured endothelial cells or upregulation of endogenous FGF-2 results in increased VEGF expression. Neutralizing monoclonal antibody to VEGF inhibits FGF-2-induced endothelial cell proliferation. Endogenous 18-kD FGF-2 production upregulates VEGF expression through extracellular interaction with cell membrane receptors; high-Mr FGF-2 (22-24-kD) acts via intracellular mechanism(s). During angiogenesis induced by FGF-2 in the mouse cornea, the endothelial cells of forming capillaries express VEGF mRNA and protein. Systemic administration of neutralizing VEGF antibody dramatically reduces FGF-2-induced angiogenesis. Because occasional fibroblasts or other cell types present in the corneal stroma show no significant expression of VEGF mRNA, these findings demonstrate that endothelial cell-derived VEGF is an important autocrine mediator of FGF-2-induced angiogenesis. Thus, angiogenesis in vivo can be modulated by a novel mechanism that involves the autocrine action of vascular endothelial cell-derived FGF-2 and VEGF.

3T3 Cells↗