Vascular chemerin from PVAT contributes to norepinephrine and serotonin-induced vasoconstriction and vascular stiffness in a sex-dependent manner

The adipokine chemerin supports normal blood pressure and contributes to adiposity-associated hypertension, evidenced by falls in mean arterial pressure in Dahl SS rats given an antisense oligonucleotide against chemerin. In humans, circulating chemerin is positively associated with hypertension and aortic stiffness. Mechanisms of chemerin's influence on vascular health and disease remain unknown. We identified chemerin production in the vasculature-the blood vessel and its perivascular adipose tissue (PVAT). Here, using RNAScope, qPCR, isometric contractility, high-frequency ultrasound imaging, and Western blot in the Dahl SS rat, we test the hypothesis that endogenous chemerin amplifies agonist-induced vasoconstriction through the chemerin1 receptor and that chemerin drives aortic stiffness in the thoracic aorta. <i>CMKLR1</i> (chemerin1) expression was higher in the media, and <i>Rarres2</i> (chemerin) expression was higher in the PVAT. Chemerin1 receptor antagonism via selective inhibitor CCX832 reduced maximal contraction to norepinephrine (NE) and serotonin (5-HT), but not angiotensin II, in isolated thoracic aorta (PVAT intact) from male Dahl SS rat. In females, CCX832 did not alter contraction to NE or 5-HT. Male, but not female, genetic chemerin knockout Dahl SS rats had lower aortic arch pulse wave velocity than wild types, indicating chemerin's role in aortic stiffness. Aortic PVAT from females expressed less chemerin protein than males, suggesting PVAT as the primary source of active chemerin. We show that chemerin made by the PVAT amplifies NE and 5-HT-induced contraction and potentially induces aortic stiffening in a sex-dependent manner, highlighting the potential for chemerin to be a key factor in blood pressure control and aortic stiffening.<b>NEW & NOTEWORTHY</b> Chemerin1 receptor inhibition reduced norepinephrine (NE) and 5-HT-induced vasoconstriction in males. Genetic chemerin knockout (KO) resulted in lower pulse wave velocity in males. Differences in chemerin abundance in aorta perivascular adipose tissue (APVAT) may explain sex-dependent role of chemerin.