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

Abstract

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.

Transcriptional profiling of the megabladder mouse: A unique model of bladder dysmorphogenesis

“…Clearly, activation of G-protein and/or the phospholipase C pathway are both capable of eliciting a variety of cellular responses through multifaceted signaling cascades. In addition, both pathways have been reported to play important roles in smooth muscle function and development (Schieffer et al, 1997;Dulin et al, 2001;Tanski et al, 2004). In a similar manner, Ca2ϩ-regulated gene transcription has been shown to be important in smooth muscle development, with recent evidence suggesting a complex interaction between Ca2ϩ signaling and the cofactors that directly effect SRF binding/transcriptional activity (Barlow et al, 2006).…”

Hyperglycemia Enhances Angiotensin II-induced Janus-activated Kinase/STAT Signaling in Vascular Smooth Muscle Cells

“…Both hyperglycemia and Ang II are capable of stimulating VSMC proliferation (2,7,8). Furthermore, Ang II stimulation of VSMC proliferation may be augmented by HG.…”

“…VSMC proliferation is also stimulated by a number of growth factors and hormones including angiotensin II (Ang II) (5)(6)(7)(8). Furthermore, Ang II stimulation of VSMC proliferation is very likely enhanced by HG because Ang II activation of mitogenactivated protein kinases (MAPKs) is increased in VSMCs cultured under HG conditions (9), and we have shown previously that activation of the MAPK pathway is essential to Ang II induction of VSMC proliferation (7,8).…”

“…Furthermore, Ang II stimulation of VSMC proliferation is very likely enhanced by HG because Ang II activation of mitogenactivated protein kinases (MAPKs) is increased in VSMCs cultured under HG conditions (9), and we have shown previously that activation of the MAPK pathway is essential to Ang II induction of VSMC proliferation (7,8). In addition to the MAPK pathway, a second pathway involved in Ang II induction of VSMC proliferation is the janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway (8).…”

Molecular and cellular mechanisms of action of angiotensin II (AT1) receptors in vascular smooth muscle

“…In some studies of rat aortic smooth muscle cells AII acts primarily as a hypertrophic agent, stimulating protein synthesis 65,66 though increased DNA synthesis and proliferation have been reported. 67 Similarly, a number of studies have reported that AII increases cell number 68,69 or thymidine incorporation 70 by cultured human aortic smooth muscle cells. In contrast cultured human saphenous vein cells did not proliferate in response to AII 71 and Patel et al 72 reported only small stimulation of DNA synthesis in cultured saphenous vein cells despite AII-induced elevation in [Ca 2+ ] i and c-fos expression in these cells.…”