Src is an important mediator of extracellular signal-regulated kinase 1/2-dependent growth signaling by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients

The role of c-Src in growth signaling by angiotensin (Ang) II was investiga ted in vascular smooth muscle cells (VSMCs) from arteries of hypertensive p atients. c-Src and extracellular signal-regulated kinase 1/2 (ERK1/2) activ ity, proto-oncogene expression, activating protein-1 (AP-1) DNA-binding act ivity, and DNA and protein synthesis were studied in Ang II-stimulated VSMC s derived from small peripheral resistance arteries of normotensive subject s (NTs, n=5) and age-matched untreated hypertensive patients (HTs, n= 10). Ang II type I (AT(2)) and type 2 (AT,) receptor status was also assessed. A ng II dose-dependently increased the synthesis of DNA and protein, with enh anced effects in VSMCs from HTs. PD 098,059, a selective inhibitor of the E RK1/2 pathway, attenuated Ang II-stimulated growth in HTs. The effects of P D 098,059 were greater in HTs than in NTs. In NTs, Ang II transiently incre ased ERK1/2 phosphorylation, whereas in HTs, Ang II-stimulated actions were augmented and sustained. PP2, a selective Src inhibitor, reduced ERK1/2 ac tivity and normalized ERK1/2 responses in HTs. Ang II-induced c-Src phospho rylation was 2- to 3-fold greater in HTs than in NTs. In HTs. but not NTs, kinase activation was followed by overexpression of c-fos and enhanced AP-I DNA-binding activity. PD 098,059 and PP2 attenuated these responses. AT(1) receptor expression was similar in NTs and HTs. In HT cells transfected wi th c-fos antisense oligodeoxynucleotide, Ang II-stimulated growth was reduc ed compared with sense oligodeoxynucleotide. Our findings suggest that augm ented Ang II-stimulated VSMC growth is mediated via hyperactivation of c-Sr c-regulated ERK1/2-dependent pathways, leading to overexpression of c-fos m RNA and enhanced AP-1 DNA-binding activity. Because AT(1) receptor expressi on was unaltered in HTs, increased Ang Il signaling may be a postreceptor p henomenon. These data define a signal transduction pathway whereby Ang II m ediates exaggerated growth in VSMCs from HTs.