Platelet C5aR1 mediates sex-specific ischemia-driven revascularization through estradiol-dependent CXCL4 release

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