p38 MAP kinase regulates vascular smooth muscle cell collagen synthesis byangiotensin II in SHR but not in WKY

Vascular remodeling in hypertension is associated with fell growth and incr eased deposition of extracellular matrix components, particularly collagen. Mechanisms underlying these processes are unclear, but MAP kinases, partic ularly ERK1/2 and p38 MAP kinase, may be important. We studied the role of ERK1/2 and p38 MAP kinase in vascular smooth muscle cell (VSMC) collagen sy nthesis and growth mediated by angiotensin (Ang) LT in spontaneously hypert ensive rats (SHR). Cultured mesenteric VSMC from Wistar-Kyoto rats and SHR were used. Phosphorylation of ERK1/2 and p38 MAP kinase were assessed by We stern blots with phosphospecific antibodies. Ang II-stimulated DNA and coll agen synthesis were determined by measuring incorporation of H-3-thymidine and H-3-proline, respectively. mRNA expression of procollagen I and III was determined by reverse transcription-polymerase chain reaction. Ang II incr eased ERK1/2 and p38 MAP kinase phosphorylation. Responses were augmented i n SIR. Effects were inhibited by irbesartan, a selective AT(1) antagonist, but not by PD123319, a selective AT(2) blocker. Ang II stimulated H-3-thymi dine and H-3-proline incorporation. These actions were enhanced 2- to 3-fol d in SHR. PD98059, selective inhibitor of the ERK1/2 pathway, attenuated An g II-induced growth and collagen effects and normalized responses in SHR. S B212190, a selective p38 MAP kinase inhibitor, did not alter Ang II-elicite d DNA synthesis but reduced collagen production and mRNA expression of proc ollagen I and III in SHR. These data demonstrate that (1) Ang II-mediated a ctivation of p38 and ERK1/2 is increased in SHR, (2) augmented growth respo nses are generated by ERK1/2-dependent, p38 MAP kinase-independent pathways , and (3) p38 MAP kinase influences Ang Ii-induced collagen production in S HR but not in Wistar-Kyoto rats. These results indicate differential roles of ERK1/2 and p38 MAP kinase in AT(1)-stimuIated VSMC growth and collagen p roduction, which may contribute to vascular remodeling in hypertension.