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Resolvin D2 prevents cardiovascular damage in angiotensin II-induced hypertension

Introduction: Vascular functional and structural alterations induced by hypertension are greatly influenced by low- grade chronic inflammation. Resolution of inflammation is orchestrated by specialized lipid pro-resolving mediators (SPMs), which derive from n3 fatty acids (PUFAs). Previous evidence suggest that SPM prevent vascular damage in several pathological situations including atherosclerosis or vascular restenosis. Among SPMs, resolvins (Rv) seem to have beneficial effects in some cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension. Objective: The aim of this study was to evaluate the effects of resolvin D2 (RvD2) in blood pressure and cardiovascular damage associated with hypertension. Material and methods: aorta, mesenteric resistance arteries (MRA), heart and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1,44mg/kg/day; for 14 days) in presence or absence of RvD2 (100ng/mice, every second day, started before AngII infusion). Blood pressure was measured by tail-cuff plethysmography. Cardiac and vascular function and structure were studied with wire and pressure myographs, confocal microscopy, histological staining, and echocardiography. Circulating leucocyte were analyzed by flow cytometry and macrophages behavior by electrophysiology. Gene expression was analyzed with RT-PCR. Results: Aorta or heart from AngII-infused mice showed altered expression of enzymes and receptors involved in SPMs biosynthesis and signaling. We also observed a downregulation of SPMs in heart tissues from these mice including 17R-RvD1 and RvE3. Treatment with RvD2 partially prevented the increase in blood pressure and in the content of circulating immune cells induced by AngII. RvD2 treatment also improved cardiac hypertrophy, fibrosis and dysfunction. Moreover, RvD2 treatment reduced vascular hypercontractility and endothelial dysfunction induced by AngII likely because of enhanced NO and PGI2 availability. RvD2 normalized AngII-induced vascular remodeling by decreasing media thickness and number of vascular smooth muscle cell, while it did not affect vascular stiffness. Finally, RvD2 reduced aortic and cardiac leukocyte infiltration and shifted macrophage phenotype towards a pro-resolving phenotype. Conclusion: Our data shows that RvD2 treatment limits the cardiovascular alterations induced by hypertension. These findings highlight that activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of cardiovascular alterations associated to hypertension.