Objective: AIP1 expression is downregulated in human
atherosclerotic plaques and global deletion of AIP1 in mice exacerbates
atherosclerosis in
ApoE-KO mouse models. However, the direct role of AIP1 in endothelium, vascular remodeling and associated
vascular diseases has not been determined. Approach and Results: We used endothelial cell (EC)-specific AIP1-deficient (AIP1-ECKO) mice to define the role of AIP1 in
vascular remodeling and intima-media thickening in a mouse carotid artery
ligation model characterized by both neointimal
hyperplasia and inward vessel remodeling. Compared to WT littermates, AIP1-ECKO mice had 2.2-fold larger intima area and 4.4-fold thicker intima as measured by intima/media ratio in arteries with more proliferating vascular smooth muscle cells (VSMCs) at week 2-4 post-injury. Increased
reactive oxygen species (ROS) in endothelium at early time points induced
inflammation and vessel dysfunction in AIP1-ECKO prior to VSMC accumulations. Moreover, knockdown of AIP1 in human EC enhanced ROS generation which was attenuated by co-silencing of NOX2. Mechanistically, AIP1 via its
proline-rich region binds to the SH3 domain of cytosolic subunit p47phox to disrupt formation of an active NOX2 complex, attenuating ROS production. Conclusion: Our study supports that AIP1 regulates
vascular remodeling with intima-media thickening by suppressing endothelial NOX2-dependent oxidative stress. Highlights: •In a carotid
ligation model, endothelial cell (EC)-specific AIP1-deficient (AIP1-ECKO) mice had much larger media area, thicker vessel wall and augmented
neointima formation.•Increased production of
reactive oxygen species in vascular EC at early time points concomitant with vessel dysfunction in AIP1-ECKO.•AIP1 via its
proline-rich region binds to the SH3 domain of cytosolic subunit p47phox to disrupt formation of an active NOX2 complex, attenuating ROS production.