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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1421.)
© 2002 American Heart Association, Inc.

Vascular Biology

Plasmin Induces Cyr61 Gene Expression in Fibroblasts Via Protease-Activated Receptor-1 and p44/42 Mitogen-Activated Protein Kinase–Dependent Signaling Pathway

Usha R. Pendurthi; Mylinh Ngyuen; Patricia Andrade-Gordon; Lars C. Petersen; L. Vijaya Mohan Rao

From Biomedical Research (U.R.P., M.N., L.V.M.R.), The University of Texas Health Center at Tyler, Tex; Drug Discovery, Johnson & Johnson Pharmaceutical & Development, L.L.C. (P.A.), Spring House, Pa; and Health Care Discovery (L.C.P.), Novo-Nordisk, Måløv, Denmark.

Correspondence to Usha R. Pendurthi, PhD, Biomedical Research, UT Health Center at Tyler, 11937 US HWY 271, Tyler, TX 75708. E-mail usha.pendurthi{at}uthct.edu

Objective— The plasminogen system has been proposed to participate in vascular remodeling and angiogenesis. Although plasmin-mediated proteolysis could contribute these processes, proteolytic targets for plasmin and their downstream effector molecules are yet to be fully defined. The aim of the present study was to elucidate potential mechanisms by which plasmin affects various cellular processes.

Methods and Results— Plasmin upregulated the expression of Cyr61, a growth factor–like gene that has been implicated in cell proliferation, adhesion, and migration. Plasmin-induced gene expression is dependent on its proteolytic activity and requires its binding to cells. Studies that used wild-type fibroblasts and fibroblasts derived from PAR-1– and PAR-2–deficient mice showed that plasmin induced Cyr61 gene expression in wild-type fibroblasts and PAR-2–deficient cells but not in PAR-1–deficient cells. Consistent with this, plasmin induced the activation of p44/42 mitogen-activated protein kinase in wild-type, PAR-2 -/- cells but not in PAR-1 -/- cells. In contrast with thrombin, plasmin failed to induce Ca²⁺ signaling in fibroblasts.

Conclusions— Plasmin induced an angiogenic and wound-healing promoter, Cyr61, in fibroblasts through activation of PAR-1. Plasmin-induced Cyr61 expression is mediated via the p44/42 mitogen-activated protein kinase pathway independent of Ca²⁺ signaling.

Key Words: plasmin • Cyr61 • protease-activated receptors

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