Autocrine TGF-beta1 mediates angiotensin II-induced proliferative response of cerebral vessels in vivo.
BACKGROUND
Angiotensin II (Ang) has been shown to induce expression of transforming growth factor-beta1 (TGF-beta1) in cardiovascular cells in vitro, but the regulation of TGF-beta1 by Ang has not been shown in cerebral vessels in vivo. Here, we tested the hypothesis that Ang promotes proliferative and fibrogenic responses in cerebral vessels through autocrine production and signaling of TGF-beta1 by vascular smooth muscle cells (VSMC).


METHODS
Rats were implanted with miniosmotic pumps that delivered a low dose of Ang (9 microg/kg/h subcutaneously for 4 to 28 days). To test for autocrine production and signaling of TGF-beta1 by VSMC, we suppressed TGF-beta1 gene expression in VSMC by infusing antisense oligodeoxynucleotide (AS-ODN) versus sense oligodeoxynucleotide (S-ODN) into the cisterna magna.


RESULTS
Systemic infusion of Ang for 28 days caused upregulation of proliferative cell nuclear antigen (PCNA) and of collagen type I in endothelium and VSMC of basilar arteries, with these changes observed as early as day 4, before the onset of hypertension. Also by day 4, significant increases in expression of TGF-beta1, TGF-beta receptors I and II, and phospho-Smad3 were observed in endothelial and VSMC layers, but plasma levels of TGF-beta1 were unchanged. With AS-ODN, but not S-ODN, TGF-beta1 was significantly reduced in VSMC but not in endothelial layers of the basilar artery, and PCNA and collagen upregulation in VSMC were essentially eliminated.


CONCLUSIONS
Autocrine TGF-beta1 signaling in VSMC is required for Ang-induced proliferative and fibrogenic responses in cerebral vessels in vivo.
Yurovsky
Vladimir V
VV
Department of Neurosurgery, University of Maryland at Baltimore, Baltimore, Maryland 21201-1595, USA.
Gerzanich
Volodymyr
V
Ivanova
Svetlana
S
Dong
Yafeng
Y
Tsymbalyuk
Orest
O
Simard
J Marc
JM
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*
D018809:Proliferating Cell Nuclear Antigen; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II