© 1999 American Heart Association, Inc.
Original Contribution |
Mitogen-Activated Protein/Extracellular Signal–Regulated Kinase Inhibition Attenuates Angiotensin II–Mediated Signaling and Contraction in Spontaneously Hypertensive Rat Vascular Smooth Muscle Cells
From the Experimental Hypertension Laboratory, Medical Research Council Multidisciplinary Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
Correspondence to R.M. Touyz MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, H2W 1R7 Quebec, Canada. E-mail touyzr{at}ircm.umontreal.ca
Abstract—This study investigates the role of extracellular signal–regulated kinases (ERKs) in angiotensin II (Ang II)–generated intracellular second messengers (cytosolic free Ca2+ concentration, ie, [Ca2+]i, and pHi) and in contraction in isolated vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY) using the selective mitogen-activated protein (MAP)/ERK inhibitor, PD98059. VSMCs from mesenteric arteries were cultured on Matrigel basement membrane matrix. These cells, which exhibit a contractile phenotype, were used to measure [Ca2+]i, pHi, and contractile responses to Ang II (10–12 to 10–6 mol/L) in the absence and presence of PD98059 (10–5 mol/L). [Ca2+]i and pHi were measured by fura-2 and BCECF methodology, respectively, and contraction was determined by photomicroscopy. Ang II–stimulated ERK activity was measured by Western blot analysis using a phospho-specific ERK-1/ERK-2 antibody and by an MAPK enzyme assay. Ang II increased [Ca2+]i and pHi and contracted cells in a dose-dependent manner. Maximum Ang II–elicited contraction was greater (P<0.05) in SHR (41.9±5.1% reduction in cell length relative to basal length) than in WKY (28.1±3.0% reduction in cell length relative to basal length). Basal [Ca2+]i, but not basal pHi, was higher in SHR compared with WKY. [Ca2+]i and pHi effects of Ang II were enhanced (P<0.05) in SHR compared with WKY (maximum Ang II–induced response [Emax] of [Ca2+]i, 576±24 versus 413±43 nmol/L; Emax of pHi, 7.33±0.01 versus 7.27±0.03, SHR versus WKY). PD98059 decreased the magnitude of contraction and attenuated the augmented Ang II–elicited contractile responses in SHR (Emax,19.3±3% reduction in cell length relative to basal length). Ang II–stimulated [Ca2+]i (Emax, 294±55 nmol/L) and pHi (Emax, 7.27±0.04) effects were significantly reduced by PD98059 in SHR. Ang II–induced ERK activity was significantly greater (P<0.05) in SHR than in WKY. In conclusion, Ang II–stimulated signal transduction and associated VSMC contraction are enhanced in SHR. MAP/ERK inhibition abrogated sustained contraction and normalized Ang II effects in SHR. These data suggest that ERK-dependent signaling pathways influence contraction and that they play a role in vascular hyperresponsiveness in SHR.
Key Words: [Ca2+]i • pHi • resistance vessel • PD98059 • hypertension
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