The Effect of Platelet-Derived Growth Factor on Tone and [Ca²⁺]i in Vascular Smooth Muscle

Abstract

Platelet derived growth factor (PDGF) is a cationic protein first described in platelets (8). PDGF is now known to be produced by a variety of cell types including endothelial cells, vascular smooth muscle cells and macrophages/monocytes (reviewed in 4). PDGF exists in multiple molecular weight isoforms which are composed of two chains (A & B) which share considerable homology. All possible dimeric forms of PDGF have been described (PGDF-AA, PDGF-BB, PDGF-AB), although the dominant isoform produced varies depending on cell type and experimental conditions (4). PDGF is a potent mitogen for vascular smooth muscle cells (4, 13) and may account for 50% of the mitogenic action of platelets (6). PDGF also contracts vascular smooth muscle in some (2, 3), but not all sites (1). PDGF-induced vasoconstriction is reported to be unaffected by antagonists of α-adrenoceptors, 5HT₂ receptors or cyclo-oxygenase (3) and presumably involves a direct action on the PDGF receptor, although the mechanism of this effect is unclear. PDGF interacts with a membrane associated receptor to induce receptor dimerization and autophosphorylation on multiple tyrosine sites (10). These phosphotyrosine residues can then interact with a variety of intracellular mediators by a process involving binding to SH2 domains in the effector proteins. Phospholipase C-γ, phosphatidyl-inositol-3 kinase, GTP-ase activating protien for p21^ras (GAP) and p21^ras all appear to be activated by PDGF in this way (10). The role of one or any of these systems in PDGF-induced contraction of vascular smooth muscle is unknown. Therefore this study examined the possible role of changes in intracellular Ca²⁺ (Cai) in the contractile action of PDGF in isolated rabbit ear artery using the fluorescent indicator fura-2 (14,15).