(Circulation. 1999;99:392-399.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Role of Extracellular Signal-Regulated Kinases in Angiotensin II–Stimulated Contraction of Smooth Muscle Cells From Human Resistance Arteries
From the Medical Research Council Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Correspondence to Rhian M. Touyz, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail touyzr{at}ircm.umontreal.ca
Background—We assessed the role of extracellular signal–regulated kinases (ERKs) in Ang II–stimulated contraction and associated signaling pathways in vascular smooth muscle cells (VSMCs) from human small arteries.
Methods and Results—VSMCs derived from resistance arteries (<300 µm in diameter) from subcutaneous gluteal biopsies of healthy subjects (n=8) were used to assess Ang II–stimulated [Ca2+]i, pHi, and contractile responses. [Ca2+]i and pHi were measured with fura 2-AM and BCECF-AM, respectively, and contraction was measured photomicroscopically in cells grown on Matrigel matrix. To determine whether tyrosine kinases and ERKs influence Ang II–stimulated responses, cells were pretreated with 10-5 mol/L tyrphostin A-23 (tyrosine kinase inhibitor) and PD98059 (MEK inhibitor). Ang II–stimulated MEK activity was determined by tyrosine phosphorylation of ERKs. The angiotensin receptor subtypes (AT1 and AT2) were assessed with [Sar1,Ile8]Ang II (a nonselective subtype antagonist), losartan (a selective AT1 antagonist), and PD123319 (a selective AT2 antagonist). Ang II dose-dependently increased [Ca2+]i (pD2=8.4±0.36, Emax=541±55 nmol/L), pHi (pD2=9.4±0.29, Emax=7.19±0.01), and contraction (pD2=9.2±0.21, Emax=36±2.2%). Ang II induced rapid tyrosine phosphorylation of ERKs, which was inhibited by PD98059. Tyrphostin A-23 and PD98059 attenuated (P<0.05) Ang II–stimulated second messengers, and PD98059 reduced Ang II–induced contraction by >50%. [Sar1,Ile8]Ang II and losartan, but not PD123319, blocked Ang II–stimulated responses.
Conclusions—These data demonstrate that in VSMCs from human peripheral resistance arteries, functional Ang II receptors of the AT1 subtype are coupled to signaling cascades involving Ca2+ and pHi pathways that are partially dependent on tyrosine kinases and ERKs. ERKs, the signaling cascades characteristically associated with cell growth, may play an important role in Ang II–stimulated contraction of human VSMCs.
Key Words: arteries • calcium • kinases • signal transduction • angiotensin
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