Chemerin stimulation of vascular function in support of blood pressure

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Project Summary Chemerin is a protein with a wide array of clinical associations but its physiological role has yet to be defined. In the epidemiological literature, circulating chemerin protein levels are increased with BMI and blood pressure. Chemerin is also used as a novel marker for metabolic syndrome which incorporates the dyslipidemia of obesity with hypertension and other cardiovascular diseases. Work looking at the association of chemerin with immune cells concludes that chemerin is pro-inflammatory. This is congruent with the fact that chemerin is associated with the inflammatory pathologies of hypertension and obesity. Other work has been performed on chemerin’s interaction with adipocytes. Chemerin is adipogenic in a paracrine fashion – meaning that chemerin is secreted by adipocytes for local travel to other adipocytes. Our lab has previously studied the interactions of chemerin with the vasculature. Chemerin is able to stimulate the smooth muscle cells in the rat aorta, superior mesenteric artery, and mesenteric resistance vessel to contract. These mesenteric resistance vessels are important to the chronic vasoconstriction observed in hypertension but are also surrounded by a perivascular adipose tissue (PVAT) that expands in the setting of obesity. We believe that the paracrine release of chemerin from this PVAT is inducing a chronic vasoconstriction in the mesenteric resistance vessels that contributes to the high blood pressure observed in those who are obese. Knockdown of chemerin in the entire rat body by antisense oligonucleotide (ASO) causes a fall in blood pressure. In a rat who has increased blood pressure and adiposity, this fall is even more dramatic. In rats, the diagnosis of obesity is poorly defined. While our data will still correlate to the human condition of obesity-associated hypertension, we are only able to make conclusions in the rat with reference to adiposity-associated hypertension. We will address the hypothesis, adiposity-associated hypertension is promoted by the release of chemerin from mPVAT (primarily adipocytes), in two aims: 1) Knockdown of chemerin reduces blood pressure in adiposity-associated hypertensive rats vs. control rat models. This addresses the in vivo interactions of chemerin, fat, and blood pressure using ASOs and the high-fat DahlS model of adiposity-associated hypertension. 2) Chemerin secreted from mPVAT in response to inflammatory mediators causes vascular smooth muscle stimulation. This addresses the specific interactions between chemerin, mPVAT adipocytes, and the smooth muscle cells of the vasculature. These results will solidify chemerin’s role as a mediator between the adipocyte and vasculature and allow us to use it as a pharmacological target in the management of obesity-associated hypertension.