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The role of aryl hydrocarbon receptor in blood pressure regulation and vascular homeostasis

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/10358

The role of aryl hydrocarbon receptor in blood pressure regulation and vascular homeostasis

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Title: The role of aryl hydrocarbon receptor in blood pressure regulation and vascular homeostasis
Author: Zhang, Nan
Advisor(s): Walker, Mary
Committee Member(s): Kanagy, Nancy
Resta, Tom
Timmins, Graham
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject(s): aryl hydrocarbon receptor
blood pressure
endothelial nitric oxide synthase
LC Subject(s): Cardiovascular system--Diseases--Etiology
Blood pressure--Regulation
Vascular endothelium--Pathophysiology
Xenobiotics--Metabolism--Regulation
Nitric oxide--Regulation
Transcription factors
Degree Level: Doctoral
Abstract: High blood pressure and endothelial dysfunction are two systemic abnormalities of the cardiovascular system that extensively contribute to the etiology of cardiovascular diseases, which represent the number one killer in the United States for decades and become more severe in developing countries. Previous studies have indicated that aryl hydrocarbon receptor (AHR), a transcription factor primarily mediating xenobiotic metabolism, plays an important role in cardiovascular development and physiology. AHR deficient mice have been demonstrated to develop hypotension at sea level and oxygen-dependent, endothelin-1 (ET-1) mediated hypertension at mild altitude. However, after generations at mild altitude, AHR deficient mice appear to acclimate to the lower atmospheric partial pressure of oxygen and exhibit normal levels of ET-1 and hypotension. Therefore, the goal of my research was to elucidate the mechanism by which endogenous AHR regulates blood pressure by studying blood pressure regulation in the absence of the AHR. I found that AHR deficient mice exhibit significantly lower systemic arterial blood pressure, dysregulated circadian blood pressure rhythm, and significantly elevated vascular endothelial nitric oxide synthase (eNOS) expression and systemic production of nitric oxide (NO). I found that treating AHR deficient mice with the NOS inhibitor, Nω-nitro-L-arginine (LNNA) failed to normalize blood pressure, suggesting that vascular eNOS over expression may not be the primary mediating factor of hypotension in AHR knockout mice. Further investigation on vascular activity ex vivo indicated increased sensitivity of vascular smooth muscle to NO which may simultaneously contribute to the hypotension in this scenario. In vitro studies using human aortic endothelial cells with AHR expression knockdown by siRNA suggested an intracellular role of endogenous AHR signaling in suppressing eNOS mRNA expression, which could be normalized by exogenous ligand activation of the residual AHR. My results suggest that AHR suppresses eNOS expression and acts to maintain basal vascular tone and normal blood pressure. Therefore, therapeutic approaches that antagonize AHR signaling could improve NO bioavailability and benefit patients with hypertension and vascular diseases commonly associated with endothelial dysfunction.
Graduation Date: July 2009
URI: http://hdl.handle.net/1928/10358

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