It is poorly understood why there is greater
cardiovascular disease risk associated with the
apolipoprotein E4 (
apoE) allele vs.
apoE3, and also greater risk with the LRP8/
apolipoprotein E receptor 2 (ApoER2) variant ApoER2-R952Q. Little is known about the function of the apoE-ApoER2 tandem outside of the central nervous system. We now report that in endothelial cells
apoE3 binding to ApoER2 stimulates endothelial
NO synthase (eNOS) and endothelial cell migration, and it also attenuates monocyte-endothelial cell adhesion. However,
apoE4 does not stimulate eNOS or endothelial cell migration or dampen cell adhesion, and alternatively it selectively antagonizes
apoE3/ApoER2 actions. The contrasting endothelial actions of
apoE4 vs.
apoE3 require the N-terminal to C-terminal interaction in
apoE4 that distinguishes it structurally from
apoE3. Reconstitution experiments further reveal that ApoER2-R952Q is a loss-of-function variant of the receptor in endothelium. Carotid artery reendothelialization is decreased in ApoER2(-/-) mice, and whereas adenoviral-driven
apoE3 expression in wild-type mice has no effect,
apoE4 impairs reendothelialization. Moreover, in a model of
neointima formation invoked by carotid artery endothelial denudation, ApoER2(-/-) mice display exaggerated
neointima development. Thus, the
apoE3/ApoER2 tandem promotes endothelial NO production, endothelial repair, and endothelial anti-inflammatory properties, and it prevents
neointima formation. In contrast,
apoE4 and ApoER2-R952Q display dominant-negative action and loss of function, respectively. Thus, genetic variants of
apoE and ApoER2 impact cardiovascular health by differentially modulating endothelial function.