SIRPA ablation inhibits intimal hyperplasia by promoting PPARγ-regulated alternative macrophage polarization

Signal regulatory protein-α (SIRPA) serves as a pivotal immune checkpoint by binding to CD47, a mechanism recognized for its antitumor potential and increasing relevance in cardiovascular diseases. However, the role and regulatory mechanisms of SIRPA in intimal hyperplasia remain poorly defined. GEO databases revealed that SIRPA expression is elevated in human atherosclerotic plaques and in-stent restenosis patients. In current study, we utilized wire-injured mouse carotid arteries and macrophages stimulated with LPS or IL-4 to demonstrate significant upregulation of SIRPA following injury and pro-inflammatory stimulation, as confirmed by RT-PCR and immunoblotting. Double immunofluorescence staining showed predominant SIRPA expression localized to macrophages in the neointima of murine arteries and plaques of human atherosclerotic coronary arteries. Global SIRPA-knockout (SIRPA-KO) mice and bone marrow transplantation from SIRPA-KO to wild-type mice showed that macrophage-specific SIRPA deletion mitigated wire injury-induced intimal hyperplasia. Loss-of-function experiments in bone marrow-derived macrophages indicated that SIRPA depletion reduced classical M1 polarization while enhancing alternative M2 activation. Subsequent coculture assays revealed that the reprogramming of macrophages due to SIRPA ablation suppressed vascular smooth muscle cell (VSMC) proliferation, migration, and dedifferentiation. Furthermore, the protective effect of SIRPA deficiency on intimal hyperplasia was attributed to enhanced alternative macrophage activation and a consequent reduction in VSMC phenotypic switching. Mechanistically, SIRPA-KO promoted alternative macrophage polarization through PPARγ upregulation, as evidenced by the reversal of this phenotype upon treatment with the PPARγ-specific antagonist G3335. Collectively, these findings unveil a previously unrecognized regulatory axis governing intimal hyperplasia and propose SIRPA as a promising therapeutic target for arterial restenosis.