The prevalence of obesity is increasing in the US population and the association between obesity and cardiovascular disease leads to excess morbidity and mortality. Vascular dysfunction is a common finding in hypertension and disorders associated with obesity, such as the metabolic syndrome. Recent evidence points to the importance of perivascular adipose tissue (PVAT) in vascular function. PVAT exerts an anticontractile effect on the vasculature. Several candidates for the adipocyte-derived relaxing factor (ADRF) have been proposed, such as adiponectin, Ang(1-7) or hydrogen peroxide, however the mechanisms of PVAT function are still under debate. In hypertension, the anticontractile effect of PVAT appears to be diminished and PVAT size is decreased. On the other hand during obesity, although PVAT size is increased, a similar loss of anticontractile effect is observed. The mechanistic differences between the dysfunction of PVAT in hypertension and obesity are unclear, and there are no studies exploring the net effect on PVAT function of overlapping hypertension and obesity, a relevant situation for the human population. Hypothesis: Imbalanced adipokine secretion leads to increased ROS production in PVAT, which in turn contributes to increased vasoconstriction in a rat model of obese hypertension.To address this hypothesis we will use a rat model that combines angiotensin II (AngII)-induced hypertension with high fat high sucrose (HFHS) choice diet-induced obesity. Control, AngII hypertensive rats and HFHS obese rats will also be used in all aims to distinguish obesity-specific from hypertension-specific findings.Specific aim 1. To test the hypothesis that imbalanced adipokine secretion increases ROS production by PVAT in obese hypertensive rats.a. Proinflammatory (leptin, resistin, visfatin) and anti-inflammatory (adiponectin) adipokines will be measured in PVAT. b. ROS production will be measured in PVAT.c. The effect of isolated adipokines on the ROS production by PVAT will be tested.Specific aim 2. To test the hypothesis that imbalanced adipokine secretion and increased ROS levels cause increased vasoconstriction of PVAT intact vessels in obese hypertensive rats.a. Contractile function of PVAT intact vessels will be evaluated.b. The effect of isolated adipokines on vasoconstriction of PVAT intact vessels will be tested.c. The effect of non-specific and specific antioxidants on vasoconstriction of PVAT intact vessels will be tested.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||07/01/2011 → 06/30/2013|