Platelet-derived growth factor inhibits basic fibroblast growth factor angiogenic properties in vitro and in vivo through its α receptor

Abstract

Basic fibroblast growth factor (bFGF) and platelet-derived growth factor-BB (PDGF-BB) modulate vascular wall cell function in vitro and angiogenesis in vivo. The aim of the current study was to determine how bovine aorta endothelial cells (BAECs) respond to the simultaneous exposure to PDGF-BB and bFGF. It was found that bFGF-dependent BAEC migration, proliferation, and differentiation into tubelike structures on reconstituted extracellular matrix (Matrigel) were inhibited by PDGF-BB. The role played by PDGF receptor ␣ (PDGF-R␣) was investigated by selective stimulation with PDGF-AA, by blocking PDGF-BB-binding to PDGF-R␣ with neomycin, or by transfecting cells with dominant-negative forms of the receptors to selectively impair either PDGF-R␣ or PDGF-R␤ function. In all cases, PDGF-R␣ impairment abolished the inhibitory effect of PDGF-BB on bFGF-directed BAEC migration. In addition, PDGF-R␣ phosphorylation was increased in the presence of bFGF and PDGF, as compared to PDGF alone, whereas mitogen-activated protein kinase phosphorylation was decreased in the presence of PDGF-BB and bFGF compared with bFGF alone. In vivo experiments showed that PDGF-BB and PDGF-AA inhibited bFGF-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane assay and that PDGF-BB inhibited bFGF-induced angiogenesis in Matrigel plugs injected subcutaneously in CD1 mice. Taken IntroductionThe endothelial layer represents a physical and chemical barrier between the vessel lumen and the underlying tissues. Endothelial cells (ECs) exert a variety of functions and modulate underlying smooth muscle cells by releasing molecules with vasoactive and growth-regulatory properties. 1 Endothelial cells present an active replication phenotype in vitro, but in vivo they are quiescent. 2 The different expression of membrane-bound receptors 3,4 and the in vivo action of specific inhibitors 5-7 may account, at least in part, for the different replication pattern observed.Basic fibroblast growth factor (bFGF) is a potent EC growth factor; it is known to induce a proangiogenic phenotype in ECs and is released under acidosis conditions that induce EC protection from apoptosis. 8 bFGF plays a critical role in physiologic and pathologic angiogenesis, including tumor angiogenesis. 9,10 It exerts its functions by direct action, 11 by inducing vascular endothelial growth factor (VEGF) synthesis, 12 or by potentiating VEGF activity. 13,14 Platelet-derived growth factor (PDGF) is a growth factor known to be active on ECs. Three PDGF isoforms have been identified as disulfide-linked dimers, namely PDGF-AA, PDGF-BB, and PDGF-AB, expressed by ECs under various conditions. 15-19 They interact with different affinity with 2 tyrosine-kinase receptors, PDGF-R␣ and PDGF-R␤, which are expressed on ECs in normal 4,20-22 and in pathologic conditions. [23][24][25][26] Recently, PDGF-C and PDGF-D isoforms were also identified. 27,28 PDGF isoforms are reported to exert mitogenic and chemotactic action on EC, although PDGF-AA appears to be less potent or inactive...

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

“…This interaction may contribute to the inhibitory effect exerted by PDGF-BB on FGF2-dependent neovascularization [169].…”

“…Since then, 22 structurally-related members of the FGF family have been identified [8]. FGFs are pleiotropic factors acting on different cell types, including www.elsevier.com/locate/cytogfr Cytokine & Growth Factor Reviews 16 (2005) [159][160][161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178] endothelial cells, following interaction with heparan-sulfate proteoglycans (HSPGs) and tyrosine kinase FGF receptors (FGFRs). To date, more than 1200 PubMed-referenced papers related to FGFs and FGFRs in endothelial cells and during neovascularization have been published.…”

Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

“…These data agree with previous observations collected on bovine aorta endothelial cells. 13 The following experiments were then carried out to identify at which level PDGF-BB exerts its modulating effects on FGF-2. Signaling molecules located at different levels onto the FGF-2 signaling pathway were analyzed.…”

“…8 Although the PDGF family is known to exert mitogenic and chemotactic action, PDGF-AA and PDGF-R␣ are less potent or even inhibitory molecules on endothelial and vascular cells, as we and others have shown. [9][10][11][12][13] We have previously observed a direct in vitro high-affinity FGF-2/PDGF-BB interaction 14 and strong FGF-2 inhibition both in vitro and in vivo in the presence of either PDGF-BB or PDGF-AA, through a PDGF-R␣-mediated mechanism. 13 Consistent with these data, other groups have shown that PDGF-R␣ may activate positive and negative signals 15 mediated by JNK-1 and p21WAF/CIP1 promoter induction.…”

“…[9][10][11][12][13] We have previously observed a direct in vitro high-affinity FGF-2/PDGF-BB interaction 14 and strong FGF-2 inhibition both in vitro and in vivo in the presence of either PDGF-BB or PDGF-AA, through a PDGF-R␣-mediated mechanism. 13 Consistent with these data, other groups have shown that PDGF-R␣ may activate positive and negative signals 15 mediated by JNK-1 and p21WAF/CIP1 promoter induction. 16 In the present study, we investigated how HUVECs respond in vitro to a FGF-2/PDGF-BB mixture compared with FGF-2 alone, and we identified a novel controlling mechanism involving FGF-R1/ PDGF-R␣ heterodimerization.…”