Exercise induced greater right ventricular hypertrophy and decreased stiffness in female mice, which was abolished by CCR2+ macrophage depletion, whereas males preferentially developed LV hypertrophy.
Does CCR2+ macrophage depletion alter sex-specific right ventricular adaptation to exercise and pressure overload in rodent models?
CCR2+ macrophages are essential for female-specific right ventricular hypertrophy and splenic responses during exercise, demonstrating sex-dependent immune-cardiac crosstalk in right ventricular adaptation.
Abstract Background Right ventricular (RV) function is the major determinant of outcomes in pulmonary hypertension (PH). The RV exhibits distinct physiologic and pathologic adaptations compared to the left ventricle (LV), and these processes are strongly influenced by sex. In health, women demonstrate superior RV contractile reserve and more efficient pulmonary vascular coupling during exercise, whereas men exhibit greater absolute hypertrophy but are more prone to maladaptation under sustained load. In PH, women are disproportionately affected yet paradoxically display more adaptive RV remodeling and improved survival despite similar afterload. The mechanisms underlying these sex-specific responses remain unclear. Cardiac macrophages regulate myocardial remodeling, but their role in sex-dependent RV adaptation to physiologic and pathologic stress is not defined. Methods We studied RV adaptation across three models: (1) voluntary wheel running in healthy mice, (2) forced treadmill exercise in healthy and Sugen-hypoxia (SuHx) PH rats, and (3) CCR2-DTR mice undergoing macrophage depletion with diphtheria toxin during exercise. Cardiac remodeling was assessed by gravimetric indices (body- and tibia-normalized weights, Fulton index), echocardiography, and spleen weight. Fibrosis and biomechanics were analyzed by Picrosirius red staining and atomic force microscopy (AFM). CCR2+ macrophages were quantified by immunofluorescence and flow cytometry. Results Female mice ran consistently more than males, while male CCR2-DTR+ mice ran less than CCR2-DTR- controls. Exercise increased RV mass in both sexes; tibia normalization confirmed significant RV hypertrophy in males and females, while LV hypertrophy was significant only in males. Fulton index increased in females but not males, and spleen weight was elevated in exercised females only. Echocardiography showed increased LV mass but preserved ejection fraction. CCR2+ macrophages increased in both ventricles with exercise, significantly in the LV, while CCR2- macrophages were unchanged. AFM revealed decreased RV stiffness in exercised females but not males; stiffness was unchanged in SuHx-PH rats regardless of exercise. In CCR2-DTR mice, CCR2+ macrophage depletion abolished exercise-induced RV hypertrophy and splenomegaly in females, while LV hypertrophy persisted in males. Conclusions These findings reveal striking sex differences in RV adaptation: females exhibit greater RV hypertrophy, immune activation, and biomechanical remodeling, while males preferentially develop LV hypertrophy. CCR2+ macrophages may be required for female-specific RV hypertrophy and splenic responses but not for male LV remodeling. This work highlights sex-dependent immune-cardiac crosstalk as a central determinant of RV adaptation, with implications for targeted therapies in PH and other pressure overload states. This abstract is funded by: Ludeman Family Center for Women’s Health Research
Bonnici et al. (Fri,) conducted a other in Pulmonary hypertension and right ventricular adaptation. Exercise and CCR2+ macrophage depletion vs. Controls was evaluated on Cardiac remodeling, fibrosis, biomechanics, and macrophage quantification. Exercise induced greater right ventricular hypertrophy and decreased stiffness in female mice, which was abolished by CCR2+ macrophage depletion, whereas males preferentially developed LV hypertrophy.
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