G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras.

The binding of vasoactive peptides to their respective G protein-coupled receptors has been implicated in the pathogenesis of vascular smooth muscle cell proliferation, leading to the development of hypertension, arteriosclerosis, and restenosis after vascular injury. We previously showed that the cytosolic tyrosine kinase pp60c-src is crucial for angiotensin II (ANG II)-induced activation of the protooncogene p21ras. Therefore, we investigated the role of pp60c-src and p21ras in rat aortic smooth muscle cell proliferation induced by several G protein-coupled receptors. ANG II, endothelin-1, or thrombin increased cell proliferation and DNA synthesis. Electroporation of anti-pp60c-src antibodies into cells abolished proliferation in response to these G protein-coupled receptor ligands but not in response to platelet-derived growth factor-BB (PDGF-BB). In contrast, electroporation of anti-p21ras antibody completely blocked DNA synthesis and cell proliferation in response to ANG II, endothelin-1, thrombin, and PDGF-BB. Our data indicate that the pp60c-src tyrosine kinase is necessary and specific for vascular smooth muscle cell proliferation and DNA synthesis in response to G protein-coupled receptors but not classic growth factor receptors.

[1]  S. Eguchi,et al.  Identification of an Essential Signaling Cascade for Mitogen-activated Protein Kinase Activation by Angiotensin II in Cultured Rat Vascular Smooth Muscle Cells , 1996, The Journal of Biological Chemistry.

[2]  M. Marrero,et al.  Ca2+ channel activation by platelet-derived growth factor-induced tyrosine phosphorylation and Ras guanine triphosphate-binding proteins in rat glomerular mesangial cells. , 1996, The Journal of clinical investigation.

[3]  M. Barone,et al.  Myc but not Fos rescue of PDGF signalling block caused by kinase-inactive Src , 1995, Nature.

[4]  G. Fager.  Thrombin and proliferation of vascular smooth muscle cells. , 1995, Circulation research.

[5]  L. Velloso,et al.  Angiotensin II induces tyrosine phosphorylation of insulin receptor substrate 1 and its association with phosphatidylinositol 3-kinase in rat heart. , 1995, The Biochemical journal.

[6]  K. Malarkey,et al.  The regulation of tyrosine kinase signalling pathways by growth factor and G-protein-coupled receptors. , 1995, The Biochemical journal.

[7]  M. Marrero,et al.  Electroporation of pp60c−src Antibodies Inhibits the Angiotensin II Activation of Phospholipase C-γ1 in Rat Aortic Smooth Muscle Cells (*) , 1995, The Journal of Biological Chemistry.

[8]  G. Condorelli,et al.  Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo , 1995, Nature Medicine.

[9]  C. Benjamin,et al.  Convergence of Angiotensin II and Platelet-derived Growth Factor Receptor Signaling Cascades in Vascular Smooth Muscle Cells (*) , 1995, The Journal of Biological Chemistry.

[10]  D. Fabbro,et al.  Platelet-derived growth factor and angiotensin II stimulate the mitogen-activated protein kinase cascade in renal mesangial cells: comparison of hypertrophic and hyperplastic agonists. , 1995, The Biochemical journal.

[11]  S. Courtneidge,et al.  Src family protein tyrosine kinases and cellular signal transduction pathways. , 1995, Current opinion in cell biology.

[12]  J. Pouysségur,et al.  Activation of Src family kinase activity by the G protein-coupled thrombin receptor in growth-responsive fibroblasts. , 1994, The Journal of biological chemistry.

[13]  S. Shukla,et al.  Electrotransjection of pp60v-src monoclonal antibody inhibits activation of phospholipase C in platelets. A new mechanism for platelet-activating factor responses. , 1994, The Journal of biological chemistry.

[14]  C. Molloy,et al.  Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. Correlation with the expression of specific endogenous growth factors and reversal by suramin. , 1994, The Journal of clinical investigation.

[15]  H. Mogami,et al.  Stimulation of calcium entry is prerequisite for DNA synthesis induced by platelet-derived growth factor in vascular smooth muscle cells. , 1993, Biochemical and biophysical research communications.

[16]  B. Payrastre,et al.  Tyrosine kinases and phosphoinositide metabolism in thrombin-stimulated human platelets. , 1993, The Biochemical journal.

[17]  J. Purkiss,et al.  Endothelin‐1 stimulated phospholipase D in A10 vascular smooth muscle derived cells is dependent on tyrosine kinase Evidence for involvement in stimulation of mitogenesis , 1993, FEBS letters.

[18]  S. Coughlin,et al.  Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. , 1993, The Journal of clinical investigation.

[19]  F. Lyall,et al.  Angiotensin II increases proto‐oncogene expression and phosphoinositide turnover in vascular smooth muscle cells via the angiotensin II AT1 receptor , 1992, Journal of hypertension.

[20]  S. Schwartz,et al.  Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. , 1992, The Journal of clinical investigation.

[21]  K. Shii,et al.  Vasoconstrictor‐induced protein‐tyrosine phosphorylation in cultured vascular smooth muscle cells , 1991, FEBS letters.

[22]  M. Daemen,et al.  Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. , 1991, Circulation research.

[23]  Y. Hirata,et al.  Endothelin is a potent mitogen for rat vascular smooth muscle cells. , 1989, Atherosclerosis.

[24]  L. Hillis,et al.  Restenosis after successful coronary angioplasty. Pathophysiology and prevention. , 1988, The New England journal of medicine.