Contrasting effects of platelet-derived growth factor (PDGF) isomers on mitogenesis, contraction and intracellular calcium concentration in human vascular smooth muscle.
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.
Hafizi
S
S
Department of Cardiothoracic Surgery, Imperial College School of Medicine, Harefield Hospital, Middlesex, UK.
Nobin
R
R
Allen
S P
SP
Chester
A H
AH
Yacoub
M H
MH
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
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