Platelet-derived growth factor receptor transactivation mediates the trophic effects of angiotensin II in vivo.
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-beta (TGF-beta) 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-beta mRNA in mesenteric arteries. Without affecting blood pressure or PDGF ligand expression, imatinib attenuated the changes in vessel morphology but further increased TGF-beta mRNA. Western blot analysis of mesenteric arterial tissue demonstrated the presence of the beta- but not the alpha-isoform of PDGFR. Phosphorylation of PDGFR-beta 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-beta gene expression.
Kelly
Darren J
DJ
University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Cox
Alison J
AJ
Gow
Renae M
RM
Zhang
Yuan
Y
Kemp
Bruce E
BE
Gilbert
Richard E
RE
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D002478:Cells, Cultured; D000068877:Imatinib Mesylate; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D000804:Angiotensin II; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor