PubMed Health⌕ Search

Biomedical subjects

I Zachary

Publications and source records attributed to I Zachary.

At least 19 recordsLinked to original sources
PubMed2003

VEGF signalling: integration and multi-tasking in endothelial cell biology.

The central role of VEGF (vascular endothelial growth factor A) in angiogenesis is dependent upon its ability to co-ordinately regulate multiple endothelial functions. The multifunctionality of VEGF at the cellular level results from its ability to initiate a diverse, complex and integrated network of signalling pathways via its major receptor, kinase-insert-domain-containing receptor (KDR). Activation of phospholipase C-gamma, protein kinase C, Ca(2+), ERK (extracellular-signal-regulated protein kinase), Akt, Src, focal adhesion kinase and calcineurin pathways has been implicated in mediating multiple VEGF functions, including survival, proliferation, migration, vascular permeability, tubulogenesis, NO and prostanoid synthesis, and gene expression. NO and prostanoids in turn play paracrine and autocrine roles in linking post-receptor signalling to biological functions. Integration between biologically important signalling cascades occurs at several points. Akt and ERK, for example, are key junction points linking together signal transduction involved in survival and NO generation, and proliferation and prostanoid biosynthesis. Together, the multiplicity, functional versatility and integration of VEGF signalling provide a useful framework for understanding the mechanisms underlying the endothelial biological response to this key factor.

Animals↗
PubMed2001

Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells.

Vascular endothelial growth factor (VEGF) stimulates the tyrosine phosphorylation of focal adhesion kinase (FAK), increases focal adhesion formation and is chemotactic for human umbilical-vein endothelial cells (HUVECs). In the present study we identified the major sites of VEGF-induced FAK tyrosine phosphorylation and investigated the mechanism mediating this pathway in the action of VEGF. VEGF increased the focal adhesion localization of FAK phosphorylated at Tyr-397 (Y397) and Y861 but stimulated a marked increase in phosphorylation at Y861 without significantly affecting the total level of phospho-Y397 FAK. Inhibition of Src with the specific inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) completely blocked VEGF-induced Y861 phosphorylation without decreasing the level of phospho-Y397 FAK. We also examined the role of Src in mediating endothelial functions of VEGF in which FAK has been implicated as having a role. PP2 markedly inhibited VEGF-induced chemotaxis and wound-healing cell migration. The Src inhibitor also decreased the anti-apoptotic effect of VEGF determined by surface staining of annexin V but did not increase FAK proteolysis or prevent the VEGF-dependent inhibition of FAK proteolysis. In contrast, the specific PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125(FAK) expression and increased FAK proteolysis but had little effect on Y861 phosphorylation. These findings identify Src-dependent FAK phosphorylation at Y861 as a novel VEGF-induced signalling pathway in endothelial cells and suggest that this pathway might be involved in the mechanisms mediating VEGF-induced endothelial cell migration and anti-apoptosis.

Apoptosis↗
PubMed2001

Cysteine-rich and basic domain HIV-1 Tat peptides inhibit angiogenesis and induce endothelial cell apoptosis.

Previous findings suggest that both the Tat polypeptide encoded by HIV-1 and Tat-derived peptides can induce angiogenesis via activation of the KDR receptor for Vascular Endothelial Growth Factor (VEGF). We identified 20 amino acids and 12 amino acid peptides corresponding to the cysteine-rich and basic domains of HIV-1 Tat which inhibited (125)I-VEGF(165) binding to KDR and neuropilin-1 (NP-1) receptors in endothelial cells. Cysteine-rich and basic Tat peptides inhibited VEGF-induced ERK activation and mitogenesis in endothelial cells, and inhibited angiogenesis in vitro at concentrations similar to those which inhibited VEGF receptor binding. These peptides also inhibited proliferation, angiogenesis, and ERK activation induced by basic fibroblast growth factor with similar potency and efficacy. Surprisingly, we found that both cysteine-rich and basic domain Tat peptides strikingly induced apoptosis in endothelial cells, independent of their effects on VEGF and bFGF. Furthermore, we found no evidence for direct biological effects of recombinant Tat on VEGF receptor binding, ERK activation, endothelial cell survival, or mitogenesis. These findings demonstrate novel properties of Tat-derived peptides and indicate that their major effect in endothelial cells is apoptosis independent of specific inhibition of VEGF receptor activation.

Amino Acid Sequence↗
PubMed2001

Peptides encoded by exon 6 of VEGF inhibit endothelial cell biological responses and angiogenesis induced by VEGF.

VEGF induces pathological angiogenesis and is an important target for the development of novel antiangiogenic molecules. In this study, we tested synthetic peptides based on the sequence of VEGF(189) for their ability to inhibit VEGF receptor binding and biological responses. We identified 12-amino acid peptides derived from exon 6 that inhibited VEGF binding to HUVECs, VEGF-stimulated ERK activation, and prostacyclin production. These peptides inhibited VEGF-induced mitogenesis, migration, and VEGF-dependent survival of endothelial cells, but caused no increase in apoptosis in the absence of VEGF. Exon 6-encoded peptides also caused a marked inhibition of VEGF-induced angiogenesis in vitro. Studies of effects of peptides on cross-linking of VEGF to its receptors and on binding of VEGF to porcine aortic endothelial cells expressing either KDR or neuropilin-1 showed that exon 6-encoded peptides effectively blocked the interaction of VEGF with both receptors. Exon 6-derived peptides caused release of bFGF from endothelial cells but inhibited bFGF-dependent ERK activation, cell proliferation and angiogenesis. Our findings indicate that VEGF exon 6-encoded peptides inhibit VEGF-induced angiogenesis, at least in part through inhibition of VEGF binding to KDR. In addition, exon 6-encoded peptides are also effective inhibitors of bFGF-mediated angiogenesis.

Angiogenesis Inhibitors↗
PubMed2001

Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family.

The central role of vascular endothelial growth factor (VEGF) in angiogenesis in health and disease makes it attractive both as a therapeutic target for anti-angiogenic drugs and as a pro-angiogenic cytokine for the treatment of ischaemic heart disease. While VEGF binds to two receptor protein tyrosine kinases, VEGFR1 (Flt-1) and VEGFR2 (KDR), most biological functions of VEGF are mediated via VEGFR2, and the role of VEGFR1 is currently unknown. Neuropilin-1, a non-tyrosine kinase transmembrane molecule, may function as a co-receptor for VEGFR2. Considerable progress has recently been made towards delineating the signal transduction pathways distal to activation of VEGFR2. Activation of the mitogen-activated protein kinase, protein kinase C and Akt pathways are all strongly implicated in mediating diverse cellular biological functions of VEGF, including cell survival, proliferation, the generation of nitric oxide and prostacyclin and angiogenesis. Upregulation of metalloproteinases, activation of focal adhesion kinase and interactions between VEGF receptors and integrins are strongly implicated in VEGF-induced endothelial cell migration. Recent findings suggest important roles for the vasodilators nitric oxide and prostacyclin, in linking post-receptor signaling networks to downstream biological effects and in mediating some in vivo endothelial functions of VEGF.

Animals↗
PubMed2001

Vascular endothelial growth factor-induced prostacyclin production is mediated by a protein kinase C (PKC)-dependent activation of extracellular signal-regulated protein kinases 1 and 2 involving PKC-delta and by mobilization of intracellular Ca2+.

We reported previously that vascular endothelial growth factor (VEGF) stimulates prostacyclin (PGI(2)) production via activation of the extracellular signal-regulated kinase (ERK) cascade. In this paper, we examined the role of protein kinase C (PKC) in this pathway. VEGF-induced PGI(2) generation and arachidonic acid release in human umbilical vein endothelial cells were inhibited by the PKC inhibitors GF109203X and calphostin C. VEGF increased PKC activity and immunoreactivity of the PKCdelta, alpha and epsilon isoforms in particulate fractions of cells. PKC inhibitors blocked VEGF-induced activation of ERK, MEK (mitogen-activated protein kinase kinase) and the cytosolic phospholipase A(2), but had little effect on ERK activation induced by basic fibroblast growth factor. GF109203X, calphostin C and the PKCdelta-selective inhibitor, rottlerin, did not inhibit activation of the KDR receptor for VEGF. Inhibition of Ca(2+) fluxes using BAPTA/AM [1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] blocked VEGF-induced PGI(2) production but did not inhibit ERK activation. Neither activation nor inhibition of the NO/cGMP pathway had any effect on VEGF induction of ERK activity and PGI(2) synthesis. Wortmannin partially inhibited VEGF stimulation of PGI(2) production, but did not inhibit VEGF-induced ERK activity. VEGF-induced ERK activation and PGI(2) production were blocked by rottlerin, and VEGF increased association of PKCdelta with Raf-1, the upstream activator of MEK. The PKC-selective inhibitor Go6976 did not inhibit ERK activation and had only a partial effect on PGI(2) production. These findings indicate that activation of PKC plays a crucial role in VEGF signalling via the ERK cascade leading to PGI(2) synthesis and suggest that the PKCdelta isoform may be a key mediator of VEGF-induced activation of the ERK pathway via increased association with Raf-1.

Calcium↗
PubMed2001

Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is essential for angiogenesis in health and pathophysiology, and it is currently a major focus for drug targeting in the development of treatments for diverse human diseases. Recently, we proposed that VEGF could also play a role as a vascular protective factor in the adult vasculature and in disease. In this model, vascular protection is defined as a VEGF-induced enhancement of endothelial functions that mediate the inhibition of vascular smooth muscle cell proliferation, enhanced endothelial cell survival, suppression of thrombosis, and anti-inflammatory effects. A feature of this model is that protective effects of VEGF are essentially independent of angiogenesis or endothelial cell proliferation. VEGF-dependent cell survival and VEGF-induced synthesis of nitric oxide and prostacyclin are likely to be key mediators of a vascular protective effect. Vascular protection should help to improve insight into the underlying mechanisms of cardiovascular actions of VEGF and prove valuable for developing novel therapeutic approaches to cardiovascular disease.

Animals↗
PubMed2001

Gene therapy for cardiovascular disease: a case for cautious optimism.

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in animal models, leading to clinical trials in ischemic heart disease. VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas VEGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI synthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene, fas ligand) or antisense oligonucleotides to c-myb, c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor kappaB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as atherosclerosis and systemic hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as familial hypercholesterolemia. The use of vasodilator gene overexpression and antisense knockdown of vasoconstrictors to reduce blood pressure in animal models of systemic and pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.

Animals↗
PubMed2000

Nuclear localization and apoptotic regulation of an amino-terminal domain focal adhesion kinase fragment in endothelial cells.

This study investigated the subcellular compartmentalization of focal adhesion kinase (FAK) fragments and their regulation during apoptosis of human umbilical vein endothelial cells. A 50 kDa NH(2)-terminal FAK fragment and a 120 kDa FAK variant were constitutively expressed and specifically found in the nuclear fraction of cells, while a 55 kDa COOH-terminal FAK fragment was only in the cytosolic fraction. FAK cleavage fragments generated during apoptosisremained in the cytosol, while p120FAK and p50 NH(2)-terminal FAK remained in the nuclear compartment. The caspase inhibitor, ZVAD-fmk, prevented the apoptosis-induced proteolysis of p125 and p120FAK, generation of the 80 kDa cleavage product, and increased expression of p50N-FAK. Western blot with phospho-specific FAK showed that nuclear p125(FAK) was phosphorylated at a significant level at Y861, while FAK phosphorylated at Y397 and Y407 was largely in the cytosol. These results indicate that FAK NH(2)- and COOH-terminal domain fragments are segregated between nuclear and cytosolic compartments in endothelial cells and suggest novel functions for the FAK NH(2)-terminal domain.

Active Transport, Cell Nucleus↗
PubMed2000

Vascular protection: A novel nonangiogenic cardiovascular role for vascular endothelial growth factor.

There is widespread interest in the use of the angiogenic cytokine, vascular endothelial growth factor (VEGF), for the treatment of cardiovascular disease. The main paradigm for VEGF cardiovascular therapy is the stimulation of "therapeutic angiogenesis" in ischemic myocardial and peripheral vascular limb disease. In this review, approaches to VEGF therapy based on the therapeutic angiogenesis model are critically assessed, and the alternative mechanism of vascular protection is advanced. Vascular protection is defined as the VEGF-induced enhancement of endothelial functions that mediate the inhibition of vascular smooth muscle cell proliferation, enhanced endothelial cell survival, suppression of thrombosis, and anti-inflammatory effects. VEGF-induced synthesis of NO and prostacyclin are both likely to be key mediators of VEGF-dependent vascular protection. Investigation into vascular protection should help us to gain insight into the underlying mechanisms of the cardiovascular actions of VEGF and should prove valuable in the development of novel therapeutic approaches based on local VEGF gene delivery.

Animals↗
PubMed1999

Differential regulation of extracellular signal-regulated protein kinases (ERKs) 1 and 2 by cAMP and dissociation of ERK inhibition from anti-mitogenic effects in rabbit vascular smooth muscle cells.

The inhibition of extracellular signal-regulated protein kinases (ERKs) is implicated in the negative regulation of vascular smooth muscle cell (VSMC) mitogenesis by cAMP-elevating agents and transforming growth factor beta(1) (TGF-beta(1)). These factors inhibited rabbit aortic VSMC mitogenesis induced by platelet-derived growth factor (PDGF)-BB by preventing the entry of cells into S-phase. cAMP-elevating agents partly inhibited the late phase (1-4 h) of activation of ERKs 1 and 2 induced by PDGF-BB without inhibiting the early phase of activity (5-15 min) and had no effect on activity induced by basic fibroblast growth factor (bFGF). In contrast, cAMP elevation caused a marked inhibition of early ERK activation induced by angiotensin II and thrombin. TGF-beta(1) had no inhibitory effect on ERK activation induced by PDGF-BB or bFGF. The inhibition of PDGF-BB-stimulated DNA synthesis by either forskolin/3-isobutyl-1-methylxanthine (IBMX) or TGF-beta(1) was not decreased when the agents were added up to 8 h after growth factor. In contrast, the selective ERK kinase inhibitor PD98059 was a weak inhibitor of DNA synthesis; a combination of PD98059 and forskolin/IBMX had an additive inhibitory effect on DNA synthesis. Forskolin/IBMX inhibited the growth factor-induced expression of c-myc mRNA and cyclin D(1) protein, and enhanced the protein expression of p27(kip1). TGF-beta(1) had no effect on the expression of c-myc or p27(kip1) and weakly attenuated the expression of cyclin D(1). These findings support the conclusion that the suppression of VSMC mitogenesis by cAMP and TGF-beta(1) is independent of ERK inhibition. Anti-mitogenic effects of cAMP might be primarily mediated by events in late G(1).

1-Methyl-3-isobutylxanthine↗
PubMed1999

Platelet-derived growth factor-BB (PDGF-BB) regulation of migration and focal adhesion kinase phosphorylation in rabbit aortic vascular smooth muscle cells: roles of phosphatidylinositol 3-kinase and mitogen-activated protein kinases.

OBJECTIVE: Phosphatidylinositol 3'-kinase (PI3-kinase) is implicated in cell migration and focal adhesion kinase (FAK) phosphorylation. In contrast, it has been proposed that mitogen-activated protein (MAP) kinases are essential for proliferation but may be dissociated from chemotactic signalling. We investigated the roles of PI3-kinase and p42/p44 MAP kinases in cell migration and FAK tyrosine phosphorylation induced by platelet-derived growth factor-BB (PDGF-BB) in rabbit aortic vascular smooth muscle cells (VSMCs). The roles of PI3-kinase and MAP kinase pathways in the chemotactic response to insulin-like growth factor-I (IGF-I) were also examined. METHODS: The roles of PI3-kinase and p42/p44 MAP kinases were assessed using the PI3-kinase inhibitors, wortmannin and LY294002, and an inhibitor of MAP kinase kinase, PD98059. PI3-kinase activity was measured by phosphatidylinositol phosphorylation in anti-phosphotyrosine immunoprecipitates and by thin layer chromatography of phosphorylated products. Phosphorylation was assessed by immunoprecipitation with anti-phosphotyrosine antibodies and Western blotting with FAK-specific antibody. Migration was evaluated in a chemotaxis chamber using polycarbonate filters with an 8-mm pore size. RESULTS: Neither wortmannin nor LY294002 significantly reduced PDGF-BB stimulation of FAK tyrosine phosphorylation, chemotaxis or immunofluorescent staining of focal adhesions in VSMCs. PD98059, a specific inhibitor of MAP kinase activation, did not inhibit FAK tyrosine phosphorylation but markedly inhibited the migratory response of VSMCs to PDGF-BB. IGF-I also stimulated migration of VSMCs, and, relative to the effect of PDGF-BB, induced smaller increases in PI3-kinase and MAP kinase activities. Both wortmannin and PD98059 partially inhibited the migratory response to IGF-I. CONCLUSIONS: PDGF-BB stimulation of both FAK tyrosine phosphorylation and migration in VSMCs are not dependent on activation of PI3-kinase. While PDGF-BB stimulation of FAK tyrosine phosphorylation is not dependent on p42/p44 MAP kinase activation, PDGF-BB and IGF-I both stimulate p42/p44 MAP kinase activity and the chemotactic response to these factors is partially dependent on MAP kinase activation.

Androstadienes↗
PubMed1999

Nitric oxide modulation of focal adhesions in endothelial cells.

A permissive role of nitric oxide (NO) in endothelial cell migration and angiogenesis promoted by vascular endothelial growth factor (VEGF), endothelin, and substance P has previously been established. The present studies were designed to examine the mechanism(s) involved in the NO effect on focal adhesions. Time-lapse videomicroscopy of human umbilical vein endothelial cells (HUVECs) plated on the silicone rubber substrate revealed that unstimulated cells were constantly remodeling the wrinkling pattern, indicative of changing tractional forces. Application of NO donors reversibly decreased the degree of wrinkling, consistent with the release of tractional forces exerted by focal adhesions and stress fibers. Morphometric and immunocytochemical analyses showed that NO inhibited adhesion and spreading of HUVECs and attenuated recruitment of paxillin to focal adhesions. NO also had a profound dose-dependent effect on the formation of stress fibers by HUVECs. De novo formation of focal adhesions in HUVECs was significantly diminished in the presence of NO donors. Migration of HUVECs showed an absolute requirement for the functional NO synthase. NO donors did not interfere with focal adhesion kinase recruitment to focal adhesions but affected the state of its tyrosine phosphorylation, as judged from the results of immunoprecipitation and immunoblotting experiments. Videomicroscopy of HUVECs presented with VEGF in a micropipette showed that the rate of cell migration was slowed down by NO synthase inhibition as well as by inhibition of tyrosine phosphorylation. Collectively, these data indicate that NO reversibly releases tractional forces exerted by spreading endothelial cells via interference with the de novo formation of focal adhesions, tyrosine phosphorylation of components of focal adhesion complexes, and assembly of stress fibers.

Cell Adhesion↗
PubMed1998

Rapid activation of the novel serine/threonine protein kinase, protein kinase D by phorbol esters, angiotensin II and PDGF-BB in vascular smooth muscle cells.

Protein kinase D (PKD) is a novel serine/threonine kinase structurally distinct from all protein kinase C (PKC) isoforms but which like classic and novel PKCs is activated by phorbol esters and diacylglycerol. This study investigated the regulation of PKD in vascular smooth muscle cells (VSMC) by physiological regulators of VSMC function and growth factors. Treatment of rabbit aortic VSMC with phorbol ester, angiotensin II and PDGF-BB all stimulated PKD activity in a time- and concentration-dependent manner in VSMC. The effect of angiotensin II was particularly rapid and potent (maximum stimulation within 1 min and at 0.5 nM). In contrast, the maximum effect of PDGF-BB was obtained after 5 min. Other factors, including basic FGF, IGF-I, IGF-II, endothelin-1 and endothelin-2, had no effect on PKD activity in VSMC. These results show for the first time that PKD activity is regulated in VSMC, and is activated by the vasoconstrictor angiotensin II. PKD may be an important mediator for the biological function(s) of one or more PKC isoforms in VSMC and/or may represent a component of a novel PKC-independent signalling pathway in VSMC.

Angiotensin II↗
PubMed1998

Cytochalasin D stimulation of tyrosine phosphorylation and phosphotyrosine-associated kinase activity in vascular smooth muscle cells.

The actin filament-disrupting agent cytochalasin D strikingly increased tyrosine phosphorylation of a 75 kDa protein (p75) in rabbit aortic vascular smooth muscle cells. The microtubule-disrupting agent, colchicine had no effect on p75 tyrosine phosphorylation. Cytochalasin D also stimulated p75-directed kinase activity as determined by kinase assays of anti-Tyr(P) immunoprecipitates. Cytochalasin D stimulated tyrosine phosphorylation of the F-actin-binding protein, p80/85 cortactin, but p75 was not immunologically related either to cortactin, the phosphatidylinositol 3'-kinase p85 alpha subunit, or the 80 kDa isoform of caldesmon. These results suggest that p75 may represent a cytochalasin D-inducible kinase or kinase-associated component and provide evidence for the existence of a potentially novel kinase pathway regulated by disruption of the actin cytoskeleton.

Actins↗
PubMed1998

Vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis in development, in cancer and in other important diseases. VEGF regulates multiple endothelial cell functions including mitogenesis, permeability, vascular tone, and the production of vasoactive molecules. VEGF is related to several polypeptides which may have different and overlapping functions. The synthesis of VEGF is regulated by hypoxia-mediated control of gene transcription, alternative mRNA splicing and proteolytic processing. The diverse biological activities of VEGF are mediated through at least two receptor protein tyrosine kinases, KDR/Flk-1 and Flt-1. Because of VEGF's central importance for pathophysiological angiogenesis, the development of antagonists for VEGF in the treatment of cancer, and the use of VEGF therapeutically in cardiovascular diseases are now the focus of major research efforts.

Animals↗
PubMed1997

Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase.

Vascular endothelial growth factor (VEGF) stimulated a time- and concentration-dependent increase in PGI2 synthesis in human umbilical vein endothelial cells with a mean maximum increase of 2-fold above basal levels at 25 ng/ml after 60 min. VEGF also rapidly stimulated the release of arachidonic acid and phosphorylation and activation of cytosolic phospholipase A2 (cPLA2). The VEGF-related factor, placenta growth factor (PIGF), had little effect on PGI2 synthesis, arachidonic acid release or cPLA2 activation. PD98059, a selective inhibitor of MAP kinase kinase, caused complete inhibition of VEGF-stimulated MAP kinase activity, PGI2 synthesis and cPLA2 gel retardation, but had no effect on VEGF-induced vWF secretion. These findings provide the first evidence that VEGF can stimulate PGI2 synthesis via cPLA2-mediated arachidonic acid release and indicate that VEGF stimulation of this biosynthetic pathway may occur, at least in part, via activation of p42/p44 MAP kinases.

Arachidonic Acid↗