Differential Gender-Dependent Patterns of Cardiac Fibrosis and Fibroblast Phenotypes in Aging Mice

Aging is characterized by physiological changes within the heart leading to fibrosis and dysfunction even in individuals without underlying pathologies. Gender has been shown to influence the characteristics of cardiac aging; however, gender-dependent cardiac fibrosis occurring with age remains largely not elucidated. Thus, broadening our understanding of this phenomenon proves necessary in order to develop novel anti-fibrotic strategies in the elderly. In this study, we aim to characterize cardiac fibrosis and cardiac fibroblast (CF) populations in aged male and female mice. Echocardiography revealed eccentric hypertrophy with left ventricular dilatation in the aged male versus concentric hypertrophy with left posterior wall thickening in the female, with preserved cardiac function in both groups. Reactive fibrosis was evidenced in the myocardium and epicardium of the aged female mice hearts whereas perivascular and replacement ones where present in the male heart. Collagen I was predominant in the aged male heart whereas collagen III was the main component in the female heart. CFs in the aged male heart were mainly recruited from resident PDGFRα ⁺ populations but not derived from epicardium as evidenced by the absence of epicardial progenitor transcription factors Tcf21, Tbx18 and Wt1. Our results present a paradigm for gender-dependent cardiac fibrosis and the origins of CFs with age. This sets forth to revisit cardiac anti-fibrotic management according to the gender in the elderly and to explore novel therapeutic targets.