Atherosclerotic progression at sites of low shear stress is attenuated by myeloid-PlexinD1 deficiency through suppression of classical macrophage polarization.

Abstract

Atherosclerosis preferentially develops at disturbed flow sites, where macrophage polarization critically determines plaque vulnerability. PlexinD1 may regulate this process by mediating M1 macrophage polarization under low and oscillatory shear stress (OSS). This study aims to investigate the role of macrophage PlexinD1 in OSS-induced atherosclerotic progression. Plasma PlexinD1 was quantified in 72 patients with acute coronary syndrome (ACS) stratified by coronary bifurcation lesion involvement. Plaques in carotid bifurcations (exposed to OSS) and those in proximal common carotid arteries (exposed to laminar shear stress, LSS) were compared to investigate the differential effects of OSS vs LSS. Myeloid-PlexinD1 knockout mice were generated to investigate its role in atherosclerosis, which was induced by exposure to a high-fat, high-cholesterol diet on an apolipoprotein E-deficient background. PlexinD1-targeted multi-modal nanoparticles were developed for imaging. PlexinD1-centric regulatory mechanisms were explored through proteomic and molecular analyses of co-cultured endothelial cells and macrophages subjected to OSS or LSS. Patients with coronary bifurcation lesions exhibited 1.32-fold higher plasma PlexinD1 levels. Human carotid bifurcation lesions demonstrated concurrently increased PlexinD1 expression, M1 macrophage polarization, and plaque vulnerability compared with plaques in common carotid arteries. In atherosclerotic mice, myeloid-PlexinD1 deletion attenuated lesions by suppressing M1 macrophage polarization. OSS down-regulated PTGS2/PGE2, thereby promoting PlexinD1/NF-κB-dependent M1 macrophage polarization. PlexinD1-targeted multi-modal imaging nanoparticles enabled in vivo identification and monitoring of bifurcation lesions. OSS drives atherosclerotic progression by suppressing endothelial PTGS2/PGE2 to promote PlexinD1/NF-κB-mediated M1 macrophage polarization. PlexinD1 represents a promising target to identify and stabilize atherosclerotic lesions.