Maresin 2 Attenuates Hypertensive Vascular Remodeling via Inhibiting Macrophage Infiltration and Pro‐fibrotic Polarization

ABSTRACT Immune‐inflammatory responses are pivotal regulators of hypertensive vascular remodeling. Specialized pro‐resolving mediators (SPMs), including Maresin 2 (MaR2), are endogenous anti‐inflammatory molecules. However, the specific role of MaR2 in regulating hypertension and vascular remodeling, as well as its underlying mechanisms, remains unclear. In this study, a murine model of hypertension was induced by continuous infusion of Angiotensin II (AngII) at 1 μg/kg/min. MaR2 intervention (2 μg/kg/day) was administered either prophylactically (before model induction) or therapeutically (after model induction). Prophylactic MaR2 effectively prevented AngII‐induced blood pressure elevation and vascular remodeling. Similarly, therapeutic administration after the establishment of hypertension with MaR2 significantly lowered blood pressure and attenuated medial thickening and fibrosis in the aorta and mesenteric arteries. Mechanistic studies revealed that MaR2 significantly inhibited macrophage infiltration and inflammatory responses within vascular tissues. Further in vitro and in vivo experiments confirmed that MaR2 effectively suppressed AngII‐induced macrophage polarization toward a pro‐fibrotic phenotype and reduced the acquisition of a myofibroblast‐like phenotype (i.e., α‐SMA expression) by macrophages by blocking the TGF‐β/Smad3 signaling pathway. Notably, pharmacological activation of TGF‐β/Smad signaling using SRI011381 partially counteracted the protective effects of MaR2 on vascular remodeling. MaR2 attenuates AngII‐induced hypertension and vascular remodeling in association with reduced vascular macrophage accumulation and suppression of macrophage pro‐fibrotic polarization, at least partly through regulation of TGF‐β/Smad3 signaling. These findings identify MaR2 as a candidate pro‐resolving intervention in an AngII‐induced murine model of hypertension and support further mechanistic and translational evaluation in hypertension‐associated vascular remodeling.