Published Online
on June 14, 2004

A more recent version of this article appeared on August 1, 2004

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Submitted on January 7, 2004
Revised on February 4, 2004

Platelet-Derived Growth Factor Receptor Transactivation Mediates the Trophic Effects of Angiotensin II In Vivo

Darren J. Kelly; Alison J. Cox; Renae M. Gow; Yuan Zhang; Bruce E. Kemp; and Richard E. Gilbert^*

From the University of Melbourne (D.J.K., A.J.C., R.M.G., Y.Z., R.E.G.), Department of Medicine, St. Vincent’s Hospital, and St. Vincent’s Institute of Medical Research (B.E.K.), Victoria, Australia.

^* To whom correspondence should be addressed. E-mail: gilbert{at}medstv.unimelb.edu.au.

Abstract--In addition to the modulation of vascular tone, angiotensin II (Ang II) has growth factor-like effects in vascular tissue. The mechanisms whereby Ang II mediates these trophic actions are incompletely understood but are thought to include effects on systemic blood pressure, stimulation of transforming growth factor- (TGF-) expression, and transactivation of growth factor receptor kinases. To investigate the role of platelet-derived growth factor receptor (PDGFR) transactivation in mediating the growth factor-like effects of Ang II we administered Ang II (200 ng/kg per minute) or saline to male Sprague-Dawley rats by osmotic minipump for 12 days and treated with imatinib mesylate, an inhibitor of the PDGFR tyrosine kinase. In addition to systolic blood pressure elevation, Ang II infusion led to increased vascular weight, media:lumen ratio, matrix expansion, and overexpression of TGF- mRNA in mesenteric arteries. Without affecting blood pressure or PDGF ligand expression, imatinib attenuated the changes in vessel morphology but further increased TGF- mRNA. Western blot analysis of mesenteric arterial tissue demonstrated the presence of the - but not the -isoform of PDGFR. Phosphorylation of PDGFR- was increased by Ang II in vascular smooth muscle cells, and this was inhibited by imatinib. The findings of attenuation of vascular hypertrophy and matrix deposition by imatinib indicate that transactivation of the PDGFR in vivo contributes to the growth factor-like effects of Ang II, independent of its hemodynamic effects or its ability to induce TGF- gene expression.

Key words: angiotensin II • platelet-derived growth factor • transforming growth factors • vascular diseases

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