Macrophage Plasticity Drives Cardiac Dysfunction in Hypertension 2253031

Introduction Chronic immune activation is a central driver of cardiovascular remodeling in hypertension (HTN), which affects ∼50% of American adults and predisposes them to heart failure. Fibrosis is a hallmark of this transition, yet the initiating immune mechanisms during the development of HTN remain poorly understood. Here, we identify a previously unrecognized macrophage fate trajectory, Macrophage-to-Myofibroblast Transition (MMT), as a key immunological mechanism linking hemodynamic stress to fibrosis in hypertensive hearts. Methods In our study, HTN was induced using the unilateral nephrectomy + aldosterone infusion + high-salt intake model for 14 days. Cardiac function was assessed via ultrasound (parasternal short-axis and apical four-chamber views) and direct left ventricular catheterization. Hearts were harvested for flow cytometry and histopathology, while mechanistic in vitro studies were conducted using RAW264.7 cells and bone marrow—derived macrophages to elucidate drivers of MMT. Results Radiotelemetry confirmed HTN in our mouse model. Despite preserved ejection fraction, direct ventricle analysis revealed impaired relaxation consistent with diastolic dysfunction. Trichrome and Sirius red staining showed profound cardiac fibrosis, and flow cytometry and fluorescence microscopy revealed a striking increase of CD68+αSMA+ MMT cells. Notably, the magnitude of this MMT population rivaled that of dedicated myofibroblasts (CD68-αSMA+) in the hearts of hypertensive mice. In vitro, IL4 and IL10 induced macrophage acquisition of αSMA and myofibroblast-like morphology, identifying these cytokines as critical mediators of MMT. Conclusion This study provides the first evidence of MMT in HTN prior to heart failure, revealing a cytokine-dependent macrophage plasticity that drives early fibrotic remodeling and impairs diastolic function. Targeting IL4/IL10-mediated macrophage reprogramming may represent a novel immunomodulatory strategy to prevent fibroinflammatory progression in hypertensive heart disease. Funding Source NIH RO1-HL146713; NIH R25-GM083247; AHA 23TPA1076467. PI-sponsored student.