title: Contrasting effects of platelet-derived growth factor (PDGF) isomers on mitogenesis, contraction and intracellular calcium concentration in human vascular smooth muscle.
abstract: 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-beta, as important role players in the development of vascular smooth muscle-mediated intimal thickening in humans.
authors.affiliation: Department of Cardiothoracic Surgery, Imperial College School of Medicine, Harefield Hospital, Middlesex, UK.
authors.forename: S
authors.initials: S
authors.lastname: Hafizi
authors.forename: R
authors.initials: R
authors.lastname: Nobin
authors.forename: S P
authors.initials: SP
authors.lastname: Allen
authors.forename: A H
authors.initials: AH
authors.lastname: Chester
authors.forename: M H
authors.initials: MH
authors.lastname: Yacoub
mesh_terms: D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology; D004247:DNA / Q000096:biosynthesis; D019332:Endothelin-1 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007536:Isomerism; D008934:Mitogens / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000737:chemistry / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D012501:Saphenous Vein / Q000166:cytology; D019284:Thapsigargin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000925:Anticoagulants; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; C095477:platelet-derived growth factor AB; D000077214:Becaplermin; D019284:Thapsigargin; D004247:DNA; D002118:Calcium