Differential ANG II-induced growth activation pathways in mesenteric artery smooth muscle cells from SHR
American Journal of Physiology. Heart and Circulatory Physiology
El Mabrouk, Mohammed, Rhian M. Touyz, and Ernesto L. Schiffrin. Differential ANG II-induced growth activation pathways in mesenteric artery smooth muscle cells from SHR. Am J Physiol Heart Circ Physiol 281: H30-H39, 2001.-Angiotensin II-induced growth signaling mechanisms were investigated in vascular smooth muscle cells (VSMCs) from mesenteric arteries of sponteneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). In WKY, angiotensin II significantly increased protein synthesis ([ 3
... hesis ([ 3 H]leucine incorporation) but not DNA synthesis ([ 3 H]thymidine incorporation). In SHR, angiotensin II increased protein and DNA synthesis. VSMCs from both strains expressed angiotensin type 1 (AT 1 ) and type 2 (AT 2 ) receptors. Losartan (an AT 1 receptor 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 protein kinase (ERK) kinase inhibitor PD-98059 blocked VSMC growth responses to angiotensin II in both strains. Angiotensin II increased ERK1/2 activation more in SHR than WKY, an effect inhibited by losartan but not PD-123319. LY-294002 [a phosphatidylinositol-3 (PI3) kinase inhibitor] blocked angiotensin II-stimulated ERK1/2 activation in SHR but not in WKY, whereas bisindolylmaleimide [a protein kinase C (PKC) inhibitor] was ineffective. In conclusion, angiotensin II stimulates VSMC proliferation via AT 1 and AT 2 receptors in SHR. In WKY, angiotensin II induces VSMC hypertrophy via AT 1 receptors. ERK1/2-dependent pathways regulated by intracellular Ca 2ϩ but not PKC mediate these effects. In SHR VSMCs, PI3 kinase plays a role in augmented angiotensin II-induced ERK1/2 phosphorylation. These angiotensin II-mediated signaling events could contribute to vascular remodeling in SHR. hypertrophy; renin-angiotensin system; signal transduction; hypertension ALTERED VASCULAR SMOOTH MUSCLE CELL (VSMC) growth may contribute to the vascular remodeling found in small arteries in hypertension. Among many factors implicated in vascular remodeling, angiotensin II (ANG II) appears to be one of the most important. This is supported by in vivo studies (31, 39) demonstrating that angiotensin-converting enzyme inhibitors or an-Address for reprint requests and other correspondence: E. L.