Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β‐Adrenergic Stimulation

Abstract

Background Biological sex is an important modifier of cardiovascular disease and women generally have better outcomes compared with men. However, the contribution of cardiac fibroblasts (CFs) to this sexual dimorphism is relatively unexplored. Methods and Results Isoproterenol (ISO) was administered to rats as a model for chronic β‐adrenergic receptor (β‐AR)‐mediated cardiovascular disease. ISO‐treated males had higher mortality than females and also developed fibrosis whereas females did not. Gonadectomy did not abrogate this sex difference. To determine the cellular contribution to this phenotype, CFs were studied. CFs from both sexes had increased proliferation in vivo in response to ISO, but CFs from female hearts proliferated more than male cells. In addition, male CFs were significantly more activated to myofibroblasts by ISO. To investigate potential regulatory mechanisms for the sexually dimorphic fibrotic response, β‐AR mRNA and PKA (protein kinase A) activity were measured. In response to ISO treatment, male CFs increased expression of β1‐ and β2‐ARs, whereas expression of both receptors decreased in female CFs. Moreover, ISO‐treated male CFs had higher PKA activity relative to vehicle controls, whereas ISO did not activate PKA in female CFs. Conclusions Chronic in vivo β‐AR stimulation causes fibrosis in male but not female rat hearts. Male CFs are more activated than female CFs, consistent with elevated fibrosis in male rat hearts and may be caused by higher β‐AR expression and PKA activation in male CFs. Taken together, our data suggest that CFs play a substantial role in mediating sex differences observed after cardiac injury.

Effects of Sex and 17 β-Estradiol on Cardiac Fibroblast Morphology and Signaling Activities In Vitro

“…Many studies have observed crosstalk in β-ARs and estrogen signaling [39]. Additionally, a recent study outlined the sex dimorphic response in CFs due to β-AR stimulation [40]. As β-blockers are already an FDA-approved treatment for many cardiovascular pathologies, including high blood pressure and heart failure, this connection offers a promising avenue of potential regulation of uncontrolled fibrosis that warrants further investigation.…”

Effects of Sex and 17β-Estradiol on Cardiac Fibroblast Morphology and Signaling Activities <em>in vitro</em>

“…Many studies have observed cross-talk in β-ARs and estrogen signaling [35]. Additionally, a recent study outlined the sex dimorphic response in CFs due to β-AR stimulation [36]. As β-blockers are already an FDA-approved treatment for many cardiovascular pathologies including high blood pressure and heart failure, this connection offers a promising avenue of potential regulation of uncontrolled fibrosis that warrants further investigation.…”

Modulation of Cardiac Fibrosis in and Beyond Cells

“…The male rats also exhibited severer cardiac hypertrophy and mortality than the females. Gonadectomy did not change cardiac fibrotic response in both sex of rats in response to isoproterenol treatment, therefore, the sex hormones did not appear to be the determinants of cardiac fibrosis although ovariectomized female rats with isoproterenol had increased mortality ( Peter et al, 2021 ). Interestingly, the cardiac fibroblasts from male rats were found to have higher levels of adrenergic receptors β1 and β2 than the female fibroblasts, which could be responsible for a stronger activation of male cardiac fibroblasts in response to isoproterenol stimulation compared to female fibroblasts ( Peter et al, 2021 ).…”

“…In animal models, there was no significant difference in cardiac fibrosis between female and male mice after acute (single dose of isoproterenol 10 mg/kg) or chronic adrenergic stimulation (infusion of isoproterenol 10 mg/kg/day for 14 days) ( Grant et al, 2020 ). However, a recent study found that male rats developed cardiac fibrosis in response to isoproterenol stimulation (4 mg/kg/day) while the females did not ( Peter et al, 2021 ). The male rats also exhibited severer cardiac hypertrophy and mortality than the females.…”

“…Recently, targeting activated cardiac fibroblasts and TIMPs have been employed to combat cardiac fibrosis ( Purcell et al, 2018 ; Aghajanian et al, 2019 ). Fibroblast functions and cardiac fibrosis can be influenced by sex differences ( Peter et al, 2021 ). Sex differences also exist in exercise-associated myocardial fibrosis ( Tahir et al, 2018 ).…”