Annexin-A1 deficiency uncovers female-specific pathways in blood pressure control and cardiovascular remodeling in mice.

Cardiovascular disease exhibits distinct sex-based differences, yet the mechanisms underlying these differences remain under-explored. The pro-resolving mediator annexin-A1 (ANXA1) is a pivotal regulator in inflammation resolution and tissue homeostasis, including within the cardiovascular system. However, the sex-specific differences in ANXA1 in blood pressure regulation have not been investigated. Here, we demonstrate that deficiency of ANXA1 exacerbates angiotensin II-induced adverse aortic and cardiac structural remodeling, mitochondrial proteome dysregulation, and impaired mitochondrial function in preclinical hypertensive models, exacerbated in females. Mechanistically, we demonstrate that estrogen upregulates ANXA1 levels, associated with dysregulation of inflammatory and mitochondrial networks, suggesting that the estrogen-ANXA1 axis plays a critical role in modulating inflammation and preventing pathological remodeling. In conclusion, this study advances the understanding of female-specific cardiac and aortic tissue and cellular alterations in hypertension, providing a platform for developing therapeutic ANXA1 mimetics that address the unique pathophysiological features of hypertension in females.