Introduction: Hallmarks of hypertension are the occurrence of small artery remodeling and endothelial dysfunction. Studies suggest that immune mechanisms play a significant role in the pathophysiology of hypertension. However, it remains uncertain whether the development of hypertension involves the early activation of immune pathways prior to the elevation of blood pressure, and if it progresses in a different way in males and females. Previous findings have identified that activation of formyl peptide receptors (FPR) in arteries is important for the temporal reorganization of actin, leading to contraction and regulation of the myogenic tone. We hypothesized that early activation of FPR-1 contributes to the development of hypertension-induced vascular dysfunction, with the subsequent FPR desensitization, and progression to vascular remodeling. We aimed to characterize the vascular function of male and female BPH/2J mice, and the role of FPR in these responses. Methods: Systolic blood pressure (SBP) was measured by carotid artery catheterization in male and female BPN/3J and BPH/2J mice (6-week- or 18-month-old). Mesenteric resistance artery (MRA) reactivity was assessed by wire myography in control conditions or after incubation with the FPR-1 antagonist CHIPS (4 µg/mL) or the FPR-2 antagonist WRW4 (10 µmol/L). Collagen alignment was quantified by second harmonic generation. SBP and MRA reactivity were also evaluated in 6-9-month-old mice treated for 14 days with CHIPS or WRW4 (1 mg/mL, s.c.) or vehicle. Data are mean±SEM and analyzed by two-way ANOVA with Tukey post-hoc (p< 0.05). Results: Phenylephrine-induced contraction was higher in MRAs from 6-week-old BPH/2J males (7.26±0.72 mN/mm*, n=9) and females (8.30±1.52mN/mm*, n=3) versus BPN/3J controls (males: 5.36±0.48mN/mm, n=7; females: 5.52±0.41mN/mm, n=7), and aging increased contraction in both strains. FPR-1 antagonism slightly reduced phenylephrine potency (pD2) in BPH/2J males (CO: 6.20±0.11; CHIPS: 5.78±0.21*, n=5-9) and females (CO: 6.14±0.01; CHIPS: 5.95±0.14**, n=3), but abolished contraction in BPN/3J males, and had no effects in BPN/3J females. FPR-2 inhibition showed similar effects. Antagonists did not alter vascular responses in 18-month-old BPH/2J mice, suggesting receptor desensitization later in life. Collagen analysis showed higher density of theta values and low-tortuosity fibers in aged BPH/2J males, while females had reduced theta density and higher tortuosity. CHIPS treatment increased SBP in BPN/3J males and tended to reduce it in BPH/2J males, suggesting a potential detrimental role of FPR-1 in hypertensive males. WRW4 treatment increased SBP in BPH/2J females and tended to lower it in BPN/3J females, suggesting a protective role of FPR-2 in hypertensive females. Conclusion: These results indicate a sex-dependent, contrasting and dynamic role of FPR-1 and FPR-2 in hypertensive BPH/2J mice, with males showing increased fiber alignment and females exhibiting disorganized collagen, contributing to differential vascular dysfunction and blood pressure regulation. Funding: 1R01HL149762; 1R21AG085331-01; AARG-NTF-23-114509. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Pernomian et al. (Fri,) studied this question.