Parturition attenuates endothelial senescence to resist nitrosative stress-induced heart failure with preserved ejection fraction in mice

Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure patients and is biased toward elderly females. Nitrosative stress-induced HFpEF animal studies fail to phenocopy this sex bias and the underlying pathological mechanisms remain elusive.- Methods In this study, we used nitrosative stress-induced HFpEF animal models and pharmacological methods to induce or reduce endothelial senescence. Findings By examining HFpEF patients’ parturition history, we found that parous women showed an observational trend toward higher myocardial microperfusion than nulliparous women, although the perfusion difference did not reach statistical significance after FDR correction. To test whether parturition affects HFpEF progression, we compared primiparous and nulliparous mice using a high-fat diet and nitrosative stress-induced HFpEF model. Relative to nulliparous mice, primiparous HFpEF mice showed higher cardiac capillary density, attenuated endothelial and cardiomyocyte senescence, and delayed diastolic dysfunction. Pharmacological modulation confirmed endothelial senescence is a prerequisite for diastolic dysfunction and cardiomyocyte senescence. Endothelial cell media assays demonstrated senescent endothelial cells induce telomeric dysfunction in cardiomyocytes. Protein microarray screening further identified CXCL10 as the key paracrine factor driving cardiomyocyte senescence. Overexpression of modified telomerase protected myocardial telomeres and restored diastolic function in male and female HFpEF mice. Interpretation These data support an important role for endothelial senescence in HFpEF pathogenesis and provide mechanistic evidence for endothelial-to-cardiomyocyte senescence signaling, although endothelial-specific causality remains to be established in vivo. Parturition is associated with reduced endothelial senescence and protection from HFpEF, and telomere reprotection may serve as a therapeutic strategy for HFpEF.