Differential ANG II-induced growth activation pathways in mesenteric artery smooth muscle cells from SHR

Angiotensin II-induced growth signaling mechanisms were investigated in vas cular smooth muscle cells (VSMCs) from mesenteric arteries of sponteneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). In WKY, angiotensin II sig nificantly increased protein synthesis ([H-3] leucine incorporation) but no t DNA synthesis ([H-3] thymidine incorporation). In SHR, angiotensin II inc reased protein and DNA synthesis. VSMCs from both strains expressed angiote nsin type 1 (AT(1)) and type 2 (AT(2)) receptors. Losartan (an AT(1) recept or antagonist) but not PD-123319 (an AT(2) receptor antagonist) attenuated angiotensin II-stimulated protein synthesis in WKY VSMCs. In SHR, losartan and PD-123319 partially inhibited angiotensin II-induced VSMC proliferation . The mitogen-activated protein kinase or extracellular signal-regulated pr otein kinase (ERK) kinase inhibitor PD-98059 blocked VSMC growth responses to angiotensin II in both strains. Angiotensin II increased ERK1/2 activati on more in SHR than WKY, an effect inhibited by losartan but not PD-123319. LY-294002 [a phosphatidylinositol-3 (PI3) kinase inhibitor] blocked angiot ensin II-stimulated ERK1/2 activation in SHR but not in WKY, whereas bisind olylmaleimide [a protein kinase C (PKC) inhibitor] was ineffective. In conc lusion, angiotensin II stimulates VSMC proliferation via AT1 and AT2 recept ors in SHR. In WKY, angiotensin II induces VSMC hypertrophy via AT1 recepto rs. ERK1/2-dependent pathways regulated by intracellular Ca2+ but not PKC m ediate these effects. In SHR VSMCs, PI3 kinase plays a role in augmented an giotensin II-induced ERK1/2 phosphorylation. These angiotensin II-mediated signaling events could contribute to vascular remodeling in SHR.