Endothelial GPR68 Is Essential for Arteriogenesis and Represents a Therapeutic Target in a Model of Peripheral Artery Disease

ABSTRACT Peripheral artery disease (PAD) is characterized by arterial narrowing that reduces limb perfusion, causing significant morbidity. The body can compensate via shear stress‐driven collateral artery growth (arteriogenesis). However, the primary receptors of mechanical forces on the endothelial cells in PAD remain poorly defined. Human phenome‑wide association study (PheWAS) shows that variants near GPR68, a gene encoding shear‐stress sensitive G protein‐coupled receptor (GPCR), are associated with increased PAD risk. To investigate the role of GPR68 in arteriogenesis in PAD, hindlimb ischemia (HLI) was employed in inducible, endothelial cell‐specific Gpr68 knockout mice (Gpr68 iECKO) as well as littermate controls. Impaired blood perfusion recovery, smaller collateral artery diameter, and exacerbated distal muscle injury were observed in Gpr68 iECKO. Mechanistically, these defects we re associated with a reduction in perivascular CCR2 + macrophage recruitment, linked to the downregulation of Spp1 , Ccl2 , and Itgb3 . Pharmacological activation of Gpr68 with its agonist Compound 71 enhances monocyte adhesion to ECs via increased SPP1 in vitro. In vivo, Compound 71 accelerates perfusion recovery and mitigates ischemic tissue damage. Our findings establish that endothelial GPR68 is a critical mediator of the inflammatory‐remodeling program essential for arteriogenesis. We propose that pharmacological activation of GPR68 represents a novel therapeutic strategy for PAD.