Abstract P238: Chemerin Is Resident To Vascular Tunicas And Contributes To Vascular Tone

Abstract

The adipokine chemerin has the potential to support blood pressure, evidenced by a fall in mean arterial pressure following knockdown of chemerin protein by whole-body antisense oligonucleotides (ASO) in rat models of normal and elevated blood pressure. While the liver is the greatest contributor of circulating chemerin, liver-specific (GalNAc) ASOs that abolished hepatic-derived chemerin did not change blood pressure in these models. Thus, other sites must produce the chemerin that supports blood pressure. Presently, we hypothesize that the vasculature—the blood vessel and its perivascular adipose tissue (PVAT)—is a source of chemerin that is independent of the liver and supports arterial tone. RNAScope®, Western blot, ASOs, and isometric contractility were used in the Dahl salt sensitive (SS) rat, male and female, on a normal diet. Species-specific ZZ probes detected Rarres2 mRNA in the smooth muscle, adventitia, and PVAT of the thoracic aorta. Chemerin protein was detected immunohistochemically in the endothelium, smooth muscle cells, adventitia, and PVAT. Chemerin colocalized with the vascular smooth muscle marker a-actin and the adipocyte marker perilipin. Importantly, chemerin protein in the aorta was not reduced when liver-derived chemerin was abolished by a liver-specific ASO against chemerin (thoracic aorta control ASO = 0.62 + 0.03; GalNAc ASO = 0.35 + 0.04; abdominal aorta control ASO = 0.38 ± 0.04, GalNAc ASO = 0.40 ± 0.22). Finally, inhibition of the receptor Chemerin1 by the receptor antagonist CCX832 resulted in aortic vasorelaxation [Media/PVAT + endothelium: -8.8 ± 3.3%; Media/PVAT - endothelium: -14.6 ± 4.2%; Media + endothelium: -1.5 ± 1.3%; and Media - endothelium: -5.1 ± 7.0%, quantified by percentage of initial wakeup to phenylephrine (-152 ± 67 mg of 1660 ± 121 mg; -93 ± 13 mg of 868 ± 171 mg, -20 ± 28 mg of 1906 ± 213 mg; and -59 ± 69 mg of 964 ± 70 mg, respectively)]. These data suggest that vessel-derived chemerin may support vascular tone locally through constitutive activation of Chemerin1 and highlights vascular chemerin as a potential therapeutic target in blood pressure regulation.