IntroductionWhile both men and women develop hypertension, leading to end-organ damage in the heart and blood vessels, well-established sex differences exist in the incidence and severity of this condition. Men typically experience a higher incidence of hypertension than women, with this disparity persisting until the sixth decade of life1. However, there is a significant gap in our understanding of the sex-specific effects of hypertension and antihypertensives, as clinical trials often overlook these differences. Recent evidence suggests that the risk of cardiovascular complications arises at a lower blood pressure (BP) in females than in males, challenging the current approach of using the same BP threshold for both sexes2. This highlights the urgent need to better understand the unique mechanisms driving hypertension and its cardiovascular complications in females as an underexplored population. Addressing this knowledge gap is critical for developing more effective, sex-specific therapeutic strategies.Inflammation may contribute to the development of hypertension-associated end-organ damage3, and there is increasing evidence that differing immunological profiles may contribute to sex differences in BP control4. Sex differences in BP responses to hypertensive stimuli, such as angiotensin II (Ang II), may be influenced by immune cells5. Moreover, the lower incidence of hypertension in females may be due to a more anti-inflammatory T-cell profile than in males4. Current anti-inflammatory drugs that target the onset of inflammation have been ineffective in reducing BP, largely attributable to their adverse effects6, suggesting that the suppression of inflammation is not a suitable approach to treating hypertension. Importantly, a failure to resolve inflammation may lead to chronic inflammation and exacerbation of the risk of cardiovascular diseases7. Targeting the resolution of inflammation may, therefore, be an alternative approach to treat hypertension-induced end-organ damage.Annexin-A1 (ANXA18) is a glucocorticoid-regulated protein9 involved in the resolution of inflammation, downstream of the activation of formyl peptide receptors (FPR) 1 and 210,11, which are G-protein coupled receptors critical to the resolution of inflammation12. ANXA1 is expressed in a wide variety of tissues, including the heart, blood vessels, liver, lungs, and spleen, and many cell types such as cardiac fibroblasts, cardiomyocytes10, vascular smooth muscle cells, endothelial cells13,14, and immune cells, with the highest levels detected in neutrophils and macrophages10. ANXA1 deficiency (ANXA1-/-) increases neutrophil migration and expression of pro-inflammatory cytokines, exacerbating inflammatory responses in several experimental disease models, including arthritis15, ulcerative colitis16, systemic lupus erythematosus17, and atherosclerosis18. Qin et al.9, have reported that a deficiency of ANXA1 increased cardiac necrosis, inflammation, hypertrophy, and fibrosis following myocardial infarction (MI). FPR1 appears to be involved in cardiomyocyte survival and the preservation of left ventricular (LV) function, while FPR2 is considered responsible for attenuation of inflammation9,19. Therefore, dual FPR1/FPR2 agonists may be useful for reducing MI injury9,19. We recently reported that the small molecule FPR1/2 agonist Compound17b attenuates hypertension, adverse cardiovascular remodeling, and dysfunction in Ang II-infused male wild-type (WT) C57BL/6 mice20. In addition, ANXA1 deficiency exacerbates adverse vascular remodeling in insulin-resistant mice21 and exacerbates abdominal aortic dissection in mice22.Taken together, these findings indicate that the endogenous FPR agonist ANXA1 is implicated in systemic aortic and cardiac organization and functionally in resolving inflammation to ultimately provide cardiovascular protection. Despite these observations, the role of ANXA1 in the regulation of BP has not been explored, nor is it known whether any of these actions are sex-dependent. We, therefore, hypothesized that deficiency of ANXA1 exacerbates BP elevation, adverse cardiovascular remodeling, dysfunction, and organ-based proteomic alterations in both male and female hypertensive mice, with a greater impact on females.ResultsImpact of Ang II-induced hypertension on the cardiovascular proteome of male and female WT and ANXA1-/- miceA detailed workflow of aortic (thoracic aorta, TA) and cardiac (LV) proteomics based on sequential extraction of tissue (n = 4–5 per group), followed by quantitative label-free tandem mass spectrometry and stringent informatics analyses, quantified ~ 3500 proteins (Fig. 1A). In TA, Ang II changed 151 and 366 proteins in male and female WT mice, respectively (P