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Contrasting effects of platelet-derived growth factor (PDGF) isomers on mitogenesis, contraction and intracellular calcium concentration in human vascular smooth muscle

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The present study was aimed at characterizing the responses of human vascular smooth muscle to all three dimeric isomers of platelet-derived growth factor (PDGF-AA, -AB and –BB) in terms of mitogenesis, contraction and intracellular calcium concentration. The potential of interaction between PDGF and endothelin-1 (ET-1) was also investigated. All three PDGF isoforms (0.1–20 ng mL−1) stimulated DNA synthesis in cultured human coronary artery and saphenous vein vascular smooth muscle cells (VSMC), measured by [3H]thymidine incorporation. PDGF-AB and -BB elicited comparable large increases in DNA synthesis of maximum 595 ± 149% (P = 0.001, n = 9) and 576 ± 17% (P < 0.001, n = 5), respectively, whereas PDGF-AA was only weakly mitogenic (61 ± 16% increase; P < 0.05, n = 3). At a threshold concentration, PDGF acted in synergy with ET-1 to enhance DNA synthesis (816 ± 337% increase; P < 0.05, n = 7). In contrast to mitogenesis, none of the three PDGF isomers had any effect on contraction of human saphenous veins in vitro, nor did they affect the contractile response to ET-1, 5-HT or the thromboxane mimetic U46619. The effects of the three PDGF isomers on intracellular calcium ([Ca2+]i) rises in cultured human VSMC were heterogeneous, with PDGF-BB inducing the largest increase in [Ca2+]i (442 ± 53 nmol L−1) vs. PDGF-AB (290 ± 28 nmol L−1), whilst PDGF-AA had no effect. Both the responses to PDGF-AB and -BB relied upon intracellular calcium release, whilst only PDGF-AB showed additional dependence on influx of extracellular calcium. In summary, PDGF is strongly mitogenic and comitogenic with ET-1, despite not being a vasoconstrictor, for human VSMC. Also, human VSMC showed heterogeneous responses to the three PDGF isoforms. These results implicate PDGF, and in particular the PDGF receptor-β, as important role players in the development of vascular smooth muscle-mediated intimal thickening in humans.
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Keywords: calcium; cell; contraction; human; platelet-derived growth factor; proliferation; vascular smooth muscle

Document Type: Original Article

Affiliations: 1: Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine at the Heart Science   Centre, Harefield Hospital, Harefield, Middlesex, UK 2: Faculty of Medicine, University of Lund, Lund, Sweden

Publication date: 1998-10-01

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