Chemerin knockout reveals sex difference in the role of chemerin in blood pressure and vascular remodeling

The adipokine chemerin contributes to vascular function, blood pressure regulation, and adiposity-associated hypertension. Mechanistic chemerin research has used three key tools: an antisense oligonucleotide (ASO) against chemerin, the Chemerin1 receptor inhibitor CCX832, and a Rarres2 knockout (KO) in Dahl SS rats. We administered the ASO to the KO rat to test that the ASO against chemerin reduced blood pressure by preventing chemerin production only. However, the ASO against chemerin lowered blood pressure both in wild-type (WT) and KO rats, indicating the ASO has off-target effects. This finding necessitated the use of CCX832 and the chemerin KO rat to understand chemerin's role in cardiovascular health and disease. Here, we test the hypothesis that CCX832 administration or genetic chemerin loss will reveal chemerin's role in driving adiposity-associated hypertension and vascular stiffness. CCX832 reduced blood pressure in high-fat diet (HFD)-induced, but not high-salt diet (HSD)-induced hypertensive males, supporting that chemerin's effects on blood pressure are obesity-related and at least in part Chemerin1-mediated. In addition, genetic chemerin loss blunted development of HFD-induced hypertension in males but, interestingly, exacerbated it in females. Aortic arch stiffening was prevented in the KO male rat on HFD, but no differences were observed in females. KO males on HFD had significantly lower collagen deposition in thoracic aorta than control diet (CD) or HFD-fed male WTs, whereas there were no significant differences among females. Our findings support chemerin as a sex-dependent driver of adiposity-associated hypertension and vascular stiffness and prompt broader investigation into chemerin's role in other vascular or sex-specific diseases.NEW & NOTEWORTHY Chemerin contributes to obesity-associated hypertension through the Chemerin1 receptor. Chemerin drives adiposity-associated hypertension in males and protects against it in females. Chemerin plays a potential role in collagen deposition and vascular stiffening in males.