Overall Hypertension is a major risk factor for premature death and disability in the United States. New approaches to therapy are needed to improve clinical management and reduce mortality and morbidity. Our Program Project is based on the assumption that redistribution of peripherally stored blood toward the heart via changes in vascular capacitance is an important factor in the pathophysiology of hypertension. Since most peripherally stored blood is in the splanchnic veins, redistribution is driven largely by reduced splanchnic venous capacitance. This can be caused by active constriction of splanchnic arteries, or active or passive constriction of splanchnic veins. Over the past five years our Program Project has focused on characterizing sympathetic neural mechanisms that regulate venous capacitance, with emphasis on differential control of arterial and venous function. Most of our work has been conducted in rodents with mineralocorticoid-salt hypertension. However, clinical hypertension is increasingly associated with obesity and especially with accumulation of inflamed visceral fat in the splanchnic region. Combined with evidence of sympathetic overactivity in obesity, this led us to hypothesize that altered sympathetic control of splanchnic arteries and veins could be a critical link between obesity and hypertension. Therefore, recently we have begun to refocus our work on a high fat feeding model of obesity-related hypertension in rodents and on complementary studies in splanchnic blood vessels and fat obtained from human patients. Over the next five years we propose to: 1) perform in vivo physiological studies in our rodent model to determine the amount, source and impact on arterial pressure of splanchnic sympathetic drive in obesity-related hypertension; 2) examine in rat and human blood vessels how inflamed visceral fat impacts sympathetic neurotransmission; and 3) establish in rat and human blood vessels the importance of both a) sympathetic drive to perivascular adipose tissue and b) a newly discovered adrenergic system endogenous to perivascular adipose tissue itself.
Overall The primary goal of this proposed Program Project is to study the mechanisms that link obesity and high blood pressure. This is a critical health issue because of the high prevalence of obesity in the United States and the fact the main cause of obesity-related morbidity and mortality is high blood pressure. The work proposed may lead to new strategies for reducing morbidity and early mortality caused by obesity and overweight.
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