on September 2, 2003
Published online before print September 2, 2003, doi: 10.1161/01.HYP.0000090322.55782.30
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Submitted on March 3, 2003
From the Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC. * To whom correspondence should be addressed. E-mail: atallant{at}wfubmc.edu.
Abstract--Angiotensin (Ang) peptides play a critical role in regulating vascular reactivity and structure. We showed that Ang-(1-7) reduced smooth muscle growth after vascular injury and attenuated the proliferation of vascular smooth muscle cells (VSMCs). This study investigated the molecular mechanisms of the antiproliferative effects of Ang-(1-7) in cultured rat aortic VSMCs. Ang-(1-7) caused a dose-dependent release of prostacyclin from VSMCs, with a maximal release of 277.9±25.2% of basal values (P<0.05) by 100 nmol/L Ang-(1-7). The cyclooxygenase inhibitor indomethacin significantly attenuated growth inhibition by Ang-(1-7). In contrast, neither a lipoxygenase inhibitor nor a cytochrome p450 epoxygenase inhibitor prevented the antiproliferative effects of Ang-(1-7). These results suggest that Ang-(1-7) inhibits vascular growth by releasing prostacyclin. Ang-(1-7) caused a dose-dependent release of cAMP, which might result from prostacyclin-mediated activation of adenylate cyclase. The cAMP-dependent protein kinase inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate attenuated the Ang-(1-7)-mediated inhibition of serum-stimulated thymidine incorporation. Finally, Ang-(1-7) inhibited Ang II stimulation of mitogen-activated protein kinase activities (ERK1/2). Incubation of VSMCs with concentrations of Ang-(1-7) up to 1 µmol/L had no effect on ERK1/2 activation. However, preincubation with increasing concentrations of Ang-(1-7) caused a dose-dependent reduction in Ang II-stimulated ERK1/2 activities. Ang-(1-7) (1 µmol/L) reduced 100 nmol/L Ang II-stimulated ERK1 and ERK2 activation by 42.3±6.2% and 41.2±4.2%, respectively (P<0.01). These results suggest that Ang-(1-7) inhibits vascular growth through the release of prostacyclin, through the prostacyclin-mediated production of cAMP and activation of cAMP-dependent protein kinase, and by attenuation of mitogen-activated protein kinase activation.
Revised on April 3, 2003
Molecular Mechanisms of Inhibition of Vascular Growth by Angiotensin-(1-7)
E. Ann Tallant* and Michelle A. Clark
Key words: angiotensin II • muscle, smooth, vascular • vasculature • peptides • prostacyclin • cyclic AMP • protein kinases
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