RT Journal Article
SR Electronic
T1 AT1 receptor antagonism is proangiogenic in the brain: BDNF a novel mediator
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.112.197483
DO 10.1124/jpet.112.197483
A1 Alhusban, Ahmed
A1 Kozak, Anna
A1 Ergul, Adviye
A1 Fagan, Susan C
YR 2012
UL http://jpet.aspetjournals.org/content/early/2012/12/04/jpet.112.197483.abstract
AB Candesartan is an angiotensin II type 1 receptor blocker (ARB) that has been to shown to limit ischemic stroke and improve stroke outcome. In experimental stroke, candesartan induces a proangiogenic effect that is partly due to vascular endothelial growth factor (VEGF). Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has been reported to have angiogenic effects and play an important role in recovery after stroke. The purpose of this investigation was to determine the role of BDNF in the proangiogenic effect of candesartan in the brain under hypertensive conditions. Accordingly, spontaneously hypertensive rats were treated with candesartan and brain tissues were collected for quantification of BDNF expression. In addition, human cerebromicrovascular endothelial cells were treated with either low dose (1ƒM) or high dose (1µM) angiotensin II alone or in combination with candesartan (0.16µM) to assess the effect of candesartan treatment and BDNF involvement in the behavior of endothelial cells. Candesartan significantly increased the expression of BDNF in the SHR (p<0.05). In addition, candesartan reversed the antiangiogenic effect of the 1µM dose of AngII (p=0.0001). The observed effects of candesartan were ablated by neutralizing the effects of BDNF. Treatment with the AT2 antagonist PD-123319 significantly reduced tube-like formation in endothelial cells. AT2 stimulation induced the BDNF expression and migration (p<0.05). In conclusion candesartan exerts a proangiogenic effect on brain microvascular endothelial cells treated with angiotensin II. This response is due to increased BDNF expression and is mediated through stimulation of the AT2 receptor.