Am J Physiol Heart Circ Physiol. 2026 Jan 9. doi: 10.1152/ajpheart.00646.2025. Online ahead of print.
ABSTRACT
Sex differences in cardiovascular disease are well documented, with females often considered hormonally protected. However, some differences persist even after menopause, indicating non-hormonal influences. Endothelial dysfunction is an early contributor to cardiovascular disease, with endothelial cell senescence playing a key role. Senescence, an irreversible cell cycle arrest, can be replicative or stress-induced. This study investigates whether sex differences in endothelial senescence exist independent of hormonal influence and vary by stimulus. Senescence was induced by replication or irradiation in female and male HUVECs (up to n=7 each) cultured under hormone-free conditions. SA-β-Gal staining, telomere length, RT-qPCR of p21, p14, p16, and crystal violet assays were used to assess senescence. Replicative senescence was analyzed across passages 1-20 and stress-induced senescence 5 days post-irradiation. Female HUVECs had a significantly longer replicative lifespan than male cells (p=0.0012) despite similar proliferation. Telomere attrition occurred faster in male cells (p=0.0034), with earlier expression of senescence markers. In contrast, after irradiation, female cells exhibited stronger senescence responses, including increased SA-β-Gal staining and elevated p21, p14, and p16 levels. This study identifies sex differences in endothelial cell senescence under hormone-free conditions, pointing to intrinsic cellular factors. While male cells exhibited earlier senescence under replicative stress, female cells were more vulnerable to stress-induced senescence. Together, these results highlight the importance of sex- and stimulus-specific mechanisms in vascular aging.
PMID:41512281 | DOI:10.1152/ajpheart.00646.2025