From Inflammation Resolution to Immune Cell Fate: Maresin 2 in Hypertensive Vascular Remodeling

Abstract

Inflammation is not simply terminated by the disappearance of an injurious stimulus; rather, its resolution is an active biological process coordinated by specialized pro-resolving mediators (SPMs) [1]. Increasing evidence has implicated SPMs in vascular inflammation, endothelial dysfunction, and hypertension [2, 3], but their potential to directly restrain vascular remodeling remains incompletely understood. In a recent issue of Acta Physiologica, Peng et al. identify Maresin 2 (MaR2) as a novel regulator of hypertensive vascular remodeling and provide evidence that the actions of MaR2 extend beyond conventional suppression of inflammation [4].

The principal contribution of this study is the identification of a link between MaR2-mediated resolution and macrophage fibrotic plasticity. Using AngII-induced hypertension, Peng and colleagues show that MaR2 not only prevents hypertension-associated medial thickening and fibrosis but also retains efficacy when administered after hypertension has been established. Importantly, the therapeutic experiments are strengthened by the inclusion of a blood-pressure–matched hydralazine group. Despite achieving comparable blood-pressure reduction, hydralazine did not reproduce the structural and phenotypic benefits of MaR2, showing that MaR2 does not simply protect the vasculature as a consequence of lowering blood pressure, but exerts additional effects within the vascular wall. This distinction is particularly important because vascular remodeling can become partially uncoupled from hemodynamic load, and therefore normalization of blood pressure does not necessarily normalize the underlying cellular and extracellular-matrix pathology. More broadly, this finding shifts the therapeutic concept from controlling the hemodynamic trigger to modifying the biological response of the vessel wall to that trigger, an important distinction for chronic vascular disease.

Mechanistically, the study moves the SPM field beyond the familiar concept of cytokine suppression toward regulation of immune-cell phenotype. RNA sequencing of bone marrow-derived macrophages identified enrichment of extracellular matrix and TGF-β-related pathways, while complementary in vivo and in vitro experiments demonstrated that MaR2 reduced macrophage accumulation and acquisition of collagen-, vimentin-, and α-SMA-associated pro-fibrotic characteristics. These observations are consistent with emerging evidence that macrophage plasticity contributes to fibrotic remodeling [5]. Indeed, recent single-cell, lineage-tracing, and parabiosis studies have provided evidence that circulating monocyte-derived macrophages can acquire myofibroblast-like characteristics during AngII-induced hypertensive cardiac fibrosis [6]. Thus, the conceptual advance of the present study is not simply the description of macrophage-to-myofibroblast-like phenotypes, but the demonstration that a pro-resolving lipid mediator may actively constrain this maladaptive immune-cell state. This raises an important conceptual possibility: resolution mediators may influence not only whether inflammation persists, but also what cellular phenotype emerges after inflammatory activation, thereby directly shaping the subsequent trajectory toward tissue repair or fibrosis.

The identification of TGF-β/Smad3 as a functional mediator further connects inflammation to fibrosis. MaR2 reduced Smad3 phosphorylation, whereas Smad3 overexpression or pharmacological activation with SRI011381 partially restored macrophage infiltration, pro-fibrotic markers, and vascular remodeling. The apparent paradox that an anti-inflammatory pro-resolving mediator suppresses TGF-β/Smad3 deserves consideration, but need not be interpreted as a contradiction. TGF-β is highly context-, cell-, and stage-dependent: although it can participate in immune regulation and tissue repair, persistent TGF-β/Smad3 signaling is a major driver of extracellular-matrix deposition and fibrotic remodeling [7]. Here, the data suggest that MaR2 may interrupt the pathological coupling between inflammatory macrophage activation and a pro-fibrotic TGF-β/Smad3 program rather than globally antagonizing the physiological functions of TGF-β. An important question for future work is therefore whether MaR2 selectively modifies pathological Smad3 activation in macrophages while preserving TGF-β-dependent reparative signaling in other vascular or stromal compartments.

Several questions nevertheless remain. Firstly, the designation of these cells as undergoing macrophage-to-myofibroblast transition should remain cautious. The observed F4/80⁺α-SMA⁺ and CD64⁺vimentin⁺ populations demonstrate acquisition of myofibroblast-associated features but do not establish cellular lineage conversion. Genetic fate-mapping approaches, ideally combined with single-cell RNA sequencing and spatial transcriptomics, will be important to distinguish true macrophage-to-myofibroblast conversion from phenotypic polarization, cell fusion, or uptake of extracellular material. This distinction is particularly relevant because recent lineage-tracing studies have demonstrated that the contribution of macrophages to fibrotic myofibroblast populations is highly context dependent [8]. Importantly, such experiments could also determine whether MaR2 merely prevents the acquisition of a pro-fibrotic state or can actively restore macrophages toward a resolution-associated phenotype once this state has been established.

Secondly, the receptor through which MaR2 acts remains a major unresolved issue. The article appropriately acknowledges this limitation, but the proposed relationship with LGR6 or GPR18 should be regarded as hypothetical. LGR6 has been implicated as a receptor for Maresin 1 [9], whereas GPR18 is established in the signaling of other SPMs; neither establishes a receptor mechanism for MaR2 in vascular macrophages [10]. Direct ligand-binding studies, receptor-selective loss-of-function experiments, and pharmacological rescue approaches will therefore be essential to define the upstream pathway linking MaR2 to Smad3 regulation.

Thirdly, the therapeutic implications deserve further exploration. The day-7 intervention demonstrates efficacy after hypertension is established, while the hydralazine comparison provides important evidence for blood-pressure-independent vascular actions. Nevertheless, future studies should determine whether MaR2 can truly reverse established structural remodeling rather than simply attenuate its progression. Baseline vascular imaging before treatment, together with measurements of arterial stiffness, endothelial-dependent relaxation, resistance-vessel function, and extracellular-matrix turnover, would help address this question.

More broadly, the study raises an intriguing possibility that individual SPMs may possess distinct “resolution signatures” extending beyond inflammation termination to the control of immune-cell fate and tissue remodeling. This concept could be tested in other vascular disorders in which inflammation and fibrosis coexist, including atherosclerosis, pulmonary hypertension, and vascular injury. Comparative studies of MaR2, MaR1, and resolvins may also determine whether different SPMs target distinct cellular compartments or remodeling programs.

Overall, Peng et al. provide an important step toward redefining SPM biology in hypertension, from passive suppression of inflammatory signals to active regulation of pathological immune-cell plasticity. The combination of a blood pressure–matched hydralazine control, macrophage phenotyping, transcriptomics, and TGF-β/Smad3 rescue experiments makes a compelling case that MaR2 has vascular actions beyond blood pressure reduction. The next challenge will be to establish its receptor, define the cellular fate of macrophages more rigorously, and determine whether this resolution–fibrosis axis can be therapeutically exploited across cardiovascular diseases (Figure 1).

The authors declare no conflicts of interest.

Maresin 2 Attenuates Hypertensive Vascular Remodeling via Inhibiting Macrophage Infiltration and Pro-fibrotic Polarization, https://doi.org/10.1111/apha.70318.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.