P38 MAP Kinase Regulates Vascular Smooth Muscle Cell (VSMC) Collagen Synthesis by Ang II in Shr But not in Wky.
Vascular remodeling in hypertension is associated with cell growth and increased deposition of extracellular matrix components, particularly collagen. Molecular mechanisms underlying these processes are unclear, but MAP kinases, particularly ERK1/2 and p38, may be important. We studied the role of ERK1/2 and p38 in vascular growth effects mediated by Ang II in SHR. Cultured mesenteric VSMC from WKY and SHR were used. Phosphorylation of ERK1/2 and p38 was assessed by Western blot using phospho-specific antibodies. c-fos mRNA expression was determined by RT-PCR. Ang II-stimulated DNA, protein and proline synthesis were assessed as indices of VSMC proliferation, hypertrophy and collagen production and were determined by measuring incorporation of 3H-thymidine, 3H-leucine and 3H-proline respectively. Ang II dose-and time-dependently increased ERK1/2 and p38 phosphorylation. Responses were increased (p<0.01) 3-4 fold in SHR. PD98059, selective MEK1/2 inhibitor, and SB202190, selective p38 inhibitor, abolished Ang II-induced ERK1/2 and p38 activation respectively. Ang II increased (p<0.05) c-fos mRNA expression in SHR (173 ±12 % of control). These actions were inhibited by PD98059, but not by SB202190. Ang II stimulated 3H-thymidine, 3H-leucine and 3H-proline incorporation. Responses were enhanced (p<0.02) 2-3 fold in SHR. PD98059 attenuated Ang II-induced growth effects and normalized responses in SHR. SB212190 did not alter Ang II-elicited DNA synthesis, but reduced (P<0.05) collagen production in SHR. Effects were inhibited by irbesartan, AT1 receptor antagonist, but not by PD123319, AT2 receptor blocker. Thus 1)Ang II-mediated activation of vascular ERK1/2 and p38 is increased in SHR, 2) augmented c-fos and growth responses are generated primarily via ERK1/2, 3) p38 influences Ang II-induced collagen production in SHR but not in WKY. In conclusion, these results indicate differential roles of ERK1/2 and p38 in AT1-stimulated VSMC growth and collagen production, which may contribute to vascular remodeling in genetic hypertension. (Supported by a research grant from Bristol-Myers Squibb/Sanofi)