Sex-specific differences in cardiovascular disease outcomes remain incompletely understood at the molecular level. Here, we identified the platelet complement receptor C5aR1 as a critical mediator of sex-specific revascularization following hindlimb ischemia through an estradiol-regulated mechanism. Ischemic tissue exhibited robust complement activation with C3b and C5a accumulation that correlated strongly with deposition of the anti-angiogenic factor CXCL4 (PF4). Mechanistically, C5a stimulation of platelets triggered CXCL4 secretion, and platelet-specific deletion of C5aR1 (using PF4-Cre-C5aR1fl/fl mice) significantly improved revascularization in male mice associated with decreased CXCL4 deposition, while sex-specific differences were not observed in cre-negative animals. Male mice exhibited substantially higher platelet C5aR1 expression and enhanced C5a-induced CXCL4 secretion compared to females, resulting in greater CXCL4 accumulation in the ischemic tissue. Importantly, estradiol stimulation of megakaryocytes suppressed C5aR1 expression during pro-platelet formation, uncovering a hormone-dependent regulatory mechanism. This estradiol-C5aR1-CXCL4 axis provides a molecular explanation for sex-specific differences in ischemic revascularization known from patient studies, as sex-specific deposition of the anti-angiogenic platelet-derived factor CXCL4 was C5aR1-dependent. These findings establish a novel and unexpected mechanistic link between sex hormones, a complement-platelet crosstalk and the angiogenic response to ischemia with potential clinical implications for sex-tailored therapeutic strategies.
Nording, H., Baron, L., Sauter, M., Hagemann, L., von Esebeck, J., Schommer, N., Duerschmied, D., Marquardt, J., Lerchenmueller, C., Zuern, C., Bibli, I., Augustin, H., Mueller, O. J., Langer, H. F.
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