Platelet-Derived Growth Factor β-Receptors Can Both Promote and Inhibit Chemotaxis in Human Vascular Smooth Muscle Cells

Clunn, Gerard F.; Refson, Jonathan; Lymn, Joanne; Hughes, Alun D.

doi:10.1161/01.atv.17.11.2622

Cited by 35 publications

(34 citation statements)

References 19 publications

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“…37 In fact, when either bFGF binding to its receptor or PDGF-R␣ signaling was impaired, the inhibitory effect of bFGF was abolished. This finding is in agreement with the known modulating role of PDGF-R␣ [38][39][40] and was further confirmed by a recent report indicating that PDGF-R␣ activates JNK-1 signaling, counteracting PDGF-R␤ activity. 41 Therefore, we have hypothesized that PDGF may inhibit bFGF-induced angiogenesis, and we have, in the current study, determined whether PDGF modulates bFGF activity on ECs in vitro and in vivo.…”

Section: Introductionsupporting

confidence: 92%

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

Marchis

Ribatti

Giampietri

et al. 2002

Blood

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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...

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Section: Introductionsupporting

confidence: 92%

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

Marchis

Ribatti

Giampietri

et al. 2002

Blood

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“…23 In brief, the upper and lower compartments of the blind-well chambers were separated by gelatin-coated polycarbonate filters. TSP-1 (10 g/mL) was added to the lower chamber and acted as the chemoattractant.…”

Section: Cell Migration Assaysmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase and Focal Adhesion Kinase Are Early Signals in the Growth Factor–Like Responses to Thrombospondin-1 Seen in Human Vascular Smooth Muscle

Lymn

Rao

Clunn

et al. 1999

ATVB

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Abstract-Thrombospondin-1 (TSP-1) is a matricellular protein that is expressed in negligible amounts in normal blood vessels but is markedly upregulated in vascular injury. Although TSP-1 can act as a pleiotropic regulator for human vascular smooth muscle cells (HVSMCs), the intracellular signaling pathways stimulated by this protein remain obscure. In cultured HVSMCs derived from saphenous vein, TSP-1 induces tyrosine phosphorylation of a number of cellular proteins, with a complex temporal pattern of activation. Immunoprecipitation techniques have identified the early tyrosine-phosphorylated signals as being the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-K) and focal adhesion kinase (FAK). Tyrosine phosphorylation of the p85 subunit of PI 3-K showed a biphasic response to TSP-1 stimulation, which corresponded to a biphasic activation of the lipid kinase. Treatment with both wortmannin and LY294002 inhibited PI 3-K activity of HVSMCs but did not affect tyrosine phosphorylation of the p85 regulatory subunit. TSP-1-stimulated FAK phosphorylation, however, was substantially reduced by these inhibitors, as was the TSP-1-induced chemotaxis of these cells. These results suggest that activation of PI 3-K is an early signal induced by TSP-1 and is critical for chemotaxis. Activation of this kinase precedes and may occur upstream from FAK phosphorylation, although the nature of the interaction between these 2 enzymes remains obscure. Key Words: thrombospondin-1 Ⅲ focal adhesion kinase Ⅲ phosphatidylinositol 3-kinase Ⅲ human vascular smooth muscle T hrombospondin-1 (TSP-1), a large, homotrimeric glycoprotein, is a member of the TSP family of matricellular proteins. This family currently consists of 5 isoforms: TSP-1 through TSP-4 and TSP-5/cartilage oligomeric matrix protein, 1 which, although implicated in a wide variety of biological processes, 2 show differential tissue expression both temporally and spatially. 3,4 TSP-1 was originally described as a product of platelet ␣-granules 5 but has since been shown to be synthesized by a number of different cell types, including vascular endothelial and smooth muscle cells. 6,7 TSP-1 is present in negligible amounts in normal human blood vessels, but the expression of this protein is markedly upregulated in injured and diseased vasculature, 8 -10 suggesting a possible role for TSP-1 in the abnormal cellular response to vascular injury.Literature evidence would suggest that TSP-1 levels are regulated by growth factors. Both platelet-derived growth factor (PDGF) and transforming growth factor-␤ (TGF-␤) have been shown to induce TSP-1 secretion from vascular smooth muscle cells (VSMCs). 11,12 TSP-1 mRNA levels have been shown to be similarly regulated. Basic fibroblast growth factor upregulates TSP-1 mRNA in 3T3 cells, 13 and PDGF induces upregulation in a manner similar to that of c-myc and c-fos, with TSP-1 being classified as an immediate early response gene. 14 These data, in conjunction with the role of TSP-1 in potentiating the chemotactic response of VS...

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“…7). In a previous report on saphenous vein-derived VSMC, PDGF-BB was reported to have a biphasic effect on PDGF-βR level and chemotaxis, but the pathways involved were not identified and the ambient glucose level not given [14].…”

Section: Discussionmentioning

confidence: 95%

“…It has been suggested that the chemoattractant effect on VSMC (saphenous vein-derived) is lost at high PDGF-BB concentrations (glucose concentration not stated) [14]. The activation state of signalling pathways depends on the balance between phosphorylation and dephosphorylation of key molecules.…”

Section: Introductionmentioning

confidence: 99%

Glucose lowers the threshold for human aortic vascular smooth muscle cell migration: inhibition by protein phosphatase-2A

2008

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Aims/hypothesis Atherosclerosis, which occurs prematurely in individuals with diabetes, incorporates vascular smooth muscle cell (VSMC) chemotaxis. Glucose, through protein kinase C-β II signalling, increases chemotaxis to low concentrations of platelet-derived growth factor (PDGF)-BB. In VSMC, a biphasic response in PDGF-beta receptor (PDGF-βR) level occurs as PDGF-BB concentrations increase. The purpose of this study was to determine whether increased concentrations of PDGF-BB and raised glucose level had a modulatory effect on the mitogen-activated protein kinase/ extracellular-regulated protein kinase pathway, control of PDGF-βR level and chemotaxis. Methods Cultured aortic VSMC, exposed to normal glucose (NG) (5 mmol/l) or high glucose (HG) (25 mmol/l) in the presence of PDGF-BB, were assessed for migration (chemotaxis chamber) or else extracted and immunoblotted. Results At concentrations of PDGF-BB <540 pmol/l, HG caused an increase in the level of PDGF-βR in VSMC (immunoblotting) versus NG, an effect that was abrogated by inhibition of aldose reductase or protein kinase C-β II . At higher concentrations of PDGF-BB (>540 pmol/l) in HG, receptor level was reduced but in the presence of aldose reductase or protein kinase C-β II inhibitors the receptor levels increased. It is known that phosphatases may be activated at high concentrations of growth factors. At high concentrations of PDGF-BB, the protein phosphatase (PP)2A inhibitor, endothall, caused an increase in PDGF-βR levels and a loss of biphasicity in receptor levels in HG. At higher concentrations of PDGF-BB in HG, the chemoattractant effect of PDGF-BB was lost (chemotaxis chamber). Under these conditions inhibition of PP2A was associated with a restoration of chemotaxis to high concentrations of PDGF-BB. Conclusion/interpretation The biphasic response in PDGF-βR level and in chemotaxis to PDGF-BB in HG is due to PP2A activation.

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Platelet-Derived Growth Factor β-Receptors Can Both Promote and Inhibit Chemotaxis in Human Vascular Smooth Muscle Cells

Cited by 35 publications

References 19 publications

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

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

Phosphatidylinositol 3-Kinase and Focal Adhesion Kinase Are Early Signals in the Growth Factor–Like Responses to Thrombospondin-1 Seen in Human Vascular Smooth Muscle

Glucose lowers the threshold for human aortic vascular smooth muscle cell migration: inhibition by protein phosphatase-2A

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