CA2-DEPENDENT MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION IN SPONTANEOUSLY HYPERTENSIVE RAT VASCULAR SMOOTH-MUSCLE DEFINES A HYPERTENSIVE SIGNAL-TRANSDUCTION PHENOTYPE()

The mechanisms responsible for altered vascular smooth muscle cell (VS MC) function in hypertension remain unknown. In the spontaneously hype rtensive rat (SHR) model of genetic hypertension, there are multiple a bnormalities in VSMC function, including increased growth, Na+-H+ exch ange, and increased signal transduction by protein kinase C. The famil y of kinases termed mitogen-activated protein (MAP) kinases has recent ly been shown to be essential mediators of growth factor signal transd uction. In the present study, alterations in MAP kinase function in th e hypertensive phenotype were investigated using early-passage SHR and Wistar-Kyoto (WKY) VSMCs stimulated with angiotensin II (Ang II, 100 nmol/L) or platelet-derived growth factor-BB (PDGF-BB, 10 ng/mL). MAP kinase activity was measured by in-gel kinase assays and Western blot analysis. Two differences between SHR and WKY rats were observed for A ng II-mediated MAP kinase activation: (1) Inactivation after Ang II st imulation was more rapid in SHR than WKY VSMCs. (2) Activity in SHR VS MCs showed a greater dependence on Ca2+ mobilization, since chelation of intracellular Ca2+ with BAPTA inhibited maximal activity by 95% in SHR VSMCs but by only 50% in WKY VSMCs. In contrast to the results wit h Ang II, no differences in PDGF-stimulated MAP kinase activity were o bserved. These findings establish activation of MAP kinase by Ang II a s a feature that distinguishes SHR VSMCs from WKY VSMCs and suggest th at differences in regulation of MAP kinase signaling may alter cellula r events that are increased in the SHR genetic model of hypertension.