Contrasting effects of FPR1 and FPR2 blockade on tissue-resident SCa-1+ endothelial progenitor cell in hypertension

Introduction: Endothelial progenitor cells (EPCs) are essential for maintaining vascular integrity, contributing to endothelial repair, angiogenesis, and the resolution of inflammation. Tissue-resident EPCs, in particular, serve as a local reservoir for vascular regeneration; however, their number and function may be compromised in hypertension, diminishing the ability of the endothelium to recover from injury. Stem cell antigen-1 (SCa-1) is a well-established EPC marker. While elevated blood pressure contributes to vascular damage, growing evidence indicates that immune-driven pathways also play a decisive role in disrupting EPC-mediated repair. Formyl peptide receptors (FPRs) are innate immune G-protein–coupled receptors expressed throughout the vasculature and within progenitor cell populations. They have recently emerged as important regulators of vascular function. Because EPC phenotype and regenerative potential are sensitive to inflammatory cues, FPR signaling represents a compelling interface between immune activation, progenitor cell dysfunction, and the progression of hypertension. We hypothesized that FPR1 and FPR2 exert distinct influences on SCa-1 + EPC populations in hypertension. Specifically, we propose that antagonizing FPR1 enhances SCa-1+ EPCs, whereas inhibiting FPR2 produces the opposite effect. Methods: En face immunofluorescence of SCa-1 and CD31 (endothelial marker) was done in aortic arches of 6-9-month-old male and female BPN/3J (normotensive) and BPH/2J (hypertensive) mice treated for 14 days with CHIPS (FPR-1 antagonist) or WRW4 (FPR-2 antagonist) (1 mg/mL, s.c.) or vehicle (veh). Data are mean±SEM and analyzed by two-way ANOVA with Tukey post-hoc (p< 0.05). Results: There was a reduction in the expression of SCa-1 in the endothelial layer of hypertensive BPH male mice when compared to BPN controls (BPH veh: 256.4±36.6U vs. BPN veh: 379.4±28.3U, n=5, p< 0.05). Treatment of BPH male mice with FPR-1 antagonist CHIPS reverted this effect (BPH CHIPS: 565.1±67.1U, n=4, p< 0.05 vs. BPH veh). This result shows that blockade of FPR1 had a protective role on tissue-resident EPCs. In hypertensive females, SCa-1 tended to reduce compared to controls (BPH veh: 476.5±92.2U vs. BPN veh: 604.4±135.1U, n=5, n.s.) and treatment with FPR2 antagonist WRW4 seems to worsen it (BPH WRW4: 354.3± 24.3, n=4, n.s. vs. BPH veh), suggesting that blockade of FPR2 may have detrimental effect on EPCs. CD31 expression was reduced in hypertensive males when compared to normotensive. Inhibition of FPR1 did not have an effect on it. There were not any changes in CD31 in BPN and BPH females treated with either vehicle or WRW4. Conclusion: These findings indicate that FPR1 and FPR2 differentially regulate tissue-resident EPCs in a sex-dependent manner, with FPR1 antagonism restoring SCa-1 expression and EPC phenotype in hypertensive males, while FPR2 blockade tends to worsen EPC impairment in hypertensive females, highlighting FPR signaling as a potential target for improving vascular repair in hypertension. Fundings: 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.