Endothelin - Mechanisms in Hypertension and Obesity

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 DESCRIPTION (provided by applicant): Mentored Phase: A long-term goal of the mentor, Dr. David Pollock, is to elucidate the role of ET-1 in salt sensitive hypertension. Recently, it was demonstrated that the interstitium of the skin is an important 4 reservoir for Na+, and defects in this storage capacity occurs in salt sensitive hypertension. While mechanisms are not fully understood, preliminary data suggest that vascular endothelial cell derived ET-1 plays a role in skin Na+ storage and clearance during a high salt intake. Therefore, the central hypothesis of the mentored phase is that increases in extrarenal vascular ET-1 influences blood pressure by increasing skin Na+ storage and clearance in response to high salt intake. To test this hypothesis, a vascular endothelial cell specific ET-1 knockout mouse (VEET KO) will be utilized. The first specific aim will determine if vascular ET-1 mediates pathways that regulate Na+ storage and clearance in response to a high salt intake. These include skin interstitial Na+ concentration, macrophages and lymphocytes, tonicity-responsive enhancer binding protein, vascular endothelial growth factor c, and lymph vessel hyperplasia. It is expected that increasing salt intake will lead to increases in each of these factors, and this will be abolished n VEET KO mice. Previous studies indicate that loss of any of these regulatory pathways results in salt sensitive hypertension, however VEET KO mice are hypotensive. It is believed that this is due to lack of ET-1 in renal vasculature, which would increase renal function will isolate the role of extrarenal vascular ET-1 in blood pressure regulation. Question 3 will address this question through the transplant of kidneys from control mice with intact vascular ET-1 into VEET KO mice, a manipulation that is expected to cause salt sensitive hypertension. Independent Phase: Several lines of evidence suggest that increased ET-1 mediates cardiovascular disease associated with obesity; however, preliminary data and previous studies on cultured adipocytes suggest that reduced ETA and/or increased ETB receptor activation on adipocytes produce a favorable environment that leads to obesity. Accordingly, the overall hypothesis of the independent phase is that an imbalance between ETA/ETB receptor signaling in adipocytes creates a favorable environment that leads to obesity. The second specific aim will determine if reductions in ETA and/or increases in ETB receptor expression and function in adipocytes can lead to obesity. This will be tested through in vitro experiments on cultured adipocytes as well as knocking out ETA receptors specifically in adipose tissue of mice. Specific aim 2 will also determine if reduced ETA and/or increases in ETB receptor expression and function occurs in obesity. This will be tested by determining if ET-1 receptor expression, binding, and signaling is altered in adipose tissue of lean and obese human subjects. The third specific aim will determine if metabolic and dietary factors, such as leptin and "western" diet, cause an imbalance of ET-1 signaling in adipose tissue. ET-1 production, as well as ET-1 receptor expression and binding will be determined in adipose tissue of ob/ob and db/db mice and animals chronically fed a high fat diet. The goals of the proposed studies will undoubtedly shed light on mechanistic pathways by which ET-1 influences blood pressure and obesity, two prevalent risk factors for cardiovascular disease.