Src-Dependent Erk1/2-Mediated Signaling Pathways and Associated Ang Ii-Stimulated Growth Responses Are Altered in Vascular Smooth Muscle Cells from Arteries of Hypertensive Patients.
Molecular mechanisms underlying vascular remodeling in human hypertension are unclear. We investigated c-Src and ERK1/2 activity, proto-oncogene expression, activating protein 1 (AP-1) DNA-binding activity, and DNA and protein synthesis in Ang II-stimulated vascular smooth muscle cells (VSMC) derived from small peripheral arteries from normotensive subjects (NT) (n=5) and age-matched untreated hypertensive patients (HT) (n=10). The media and media:lumen ratio were greater (p<0.05) in arteries from HT than NT, indicating vascular remodeling. Ang II-dose-dependently increased synthesis of DNA and protein, with enhanced effects (p<0.01) in VSMCs from HT. PD98059, a selective inhibitor of the ERK1/2 pathway, attenuated (p<0.01) Ang II-stimulated growth. PD98059 effects were greater in HT than NT. In NT, Ang II transiently increased ERK1/2 phosphorylation. In HT, Ang II-stimulated ERK1/2 activation was significantly augmented (p<0.05 vs NT) and sustained. PP2, a selective Src inhibitor, reduced ERK1/2 activity and normalized responses in HT. Ang II-induced c-Src phosphorylation was 2-3 fold greater in HT than NT. In HT, kinase activation was followed by overexpression of c-fos mRNA and enhanced AP-1 DNA-binding activity. PD98059 attenuated these responses. In HT cells transfected with c-fos antisense oligodeoxynucleotide (ODN), Ang II-stimulated DNA synthesis was reduced compared with sense ODN. These novel findings suggest that vascular remodeling is associated with augmented Ang II-stimulated VSMC growth, which is mediated via hyperactivation of c-Src-regulated, ERK1/2-dependent pathways leading to overexpression of c-fos mRNA and enhanced AP-1 DNA-binding activity. Our data define a signal transduction pathway in VSMCs that could contribute to structural changes and vascular remodeling in essential hypertension.