Thrombin and Proliferation of Vascular Smooth Muscle Cells

Abstract

Thrombin is a well-established promoter of vascular SMC proliferation in vitro. A similar role has been suggested but not yet proven in vivo. The effect is mediated via selective receptors expressed on vascular SMCs in vitro. Activation of the thrombin receptor leads to a number of intracellular signaling events as well as to stimulation of endogenous PDGF–A chain and bFGF production. The proto-oncogenes c- fos and c- myc , which code for nuclear proteins needed for the induction of proliferation, are induced by PDGF and bFGF. Both growth factors activate protein kinase C. Thrombin rapidly induces only PLC and c- fos but does not activate protein kinase C. Thrombin-induced receptor activation and intracellular signaling are prevented by substances that block the catalytic and/or receptor binding domains of thrombin. These substances also block thrombin-induced expression of PDGF and bFGF. Furthermore, thrombin-induced proliferation of vascular SMCs is blocked by antibodies to PDGF and FGF. Thus, the possibility must be considered that thrombin influences proliferation of susceptible SMCs by inducing an autocrine or paracrine stimulation via PDGF and/or bFGF. Thrombin has important roles in wound healing: promoting the coagulation of blood, accumulation of inflammatory cells, and proliferation of mesenchymal cells. Enzymatically active thrombin (α-thrombin) is formed from the circulating precursor prothrombin by hydrolytic cleavage (reviewed in Reference 11 ). This hydrolysis is initially slow and catalyzed only by factor Xa. Subsequently, α-thrombin activates factor V, which operates as a cofactor to factor Xa and accelerates the formation of α-thrombin. Furthermore, factor VIII is activated by α-thrombin to participate in the production of more factor Xa. α-Thrombin belongs to the superfamily of serine proteases and cleaves its target proteins C-terminally to R (one-letter code for arginine) residues. Structural studies (reviewed in Reference 22 ) have revealed a sequence in α-thrombin in which …