Vascular remodeling is a typical feature of vascular diseases, such as atherosclerosis, aneurysms or restenosis. Excessive inflammation is a key mechanism underlying vascular remodeling via the modulation of vascular fibrosis, phenotype and function. Recent evidence suggests that not only augmented inflammation but unresolved inflammation might also contribute to different aspects of vascular diseases. Resolution of inflammation is mediated by a family of specialized pro-resolving mediators (SPMs) that limit immune cell infiltration and initiate tissue repair mechanisms. SPMs (lipoxins, resolvins, protectins, maresins) are generated from essential polyunsaturated fatty acids. Synthases and receptors for SPMs were initially described in immune cells, but they are also present in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), where they regulate processes important for vascular physiology, such as EC activation and VSMC phenotype. Evidence from genetic models targeting SPM pathways and pharmacological supplementation with SPMs have demonstrated that these mediators may play a protective role against the development of vascular remodeling in atherosclerosis, aneurysms and restenosis. This review focuses on the latest advances in understanding the role of SPMs in vascular cells and their therapeutic effects in the vascular remodeling associated with different cardiovascular diseases.

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BACKGROUND: Resolution of inflammation is orchestrated by specialized pro-resolving mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension. METHODS: Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with Angiotensin II (AngII 1.44 mg/kg/day, 14 days) in presence or absence of RvD2 (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion. RESULTS: Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype. CONCLUSIONS: There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.

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.