ApoE, ApoER2, and the Regulation of Endothelial Cell Function
Cardiovascular disease risk is greater in individuals with the apolipoprotein E (ApoE) allele ApoE4 versus ApoE3, and this is not explained by differences in lipid profiles. A point mutant of the ApoE receptor ApoER2, ApoER2-R952Q, is also associated with greater cardiovascular disease risk, suggesting a role for ApoER2 in vascular health and disease. However, how ApoE, ApoER2, and their variants influence cardiovascular health and disease is poorly understood. We discovered in cultured endothelial cells that ApoE3 activates endothelial NO synthase (eNOS) and thereby stimulates endothelial cell migration, and that both processes require ApoER2. In contrast, ApoE4 is incapable of activating eNOS and in fact blunts ApoE3 activation of eNOS migration. In eNOS-expressing 3T3 cells, we also found that in contrast to wild-type ApoER2, ApoER2-R952Q is incapable of mediating ApoE3 activation of eNOS. Furthermore, we have determined that LDLR-/-;ApoER2-/- mice have markedly worse atherosclerosis than LDLR-/-, and in preliminary studies ApoER2-/- have impaired reendothelialization. The Overall Goal of this project is to determine how ApoE, ApoER2 and their variants influence endothelial cell function, and the implications of these processes in vascular health and disease. The first aim is to identify the molecular basis for ApoE-ApoER2 function in endothelial cells. The roles of adaptor proteins for ApoER2 and for kinase signaling in ApoE3/ApoER2 activation of eNOS were tested. The basis for impaired signaling by ApoE4 will also be explored. The second aim is to determine how ApoE and ApoER2 influence endothelial cell phenotype in vivo. Carotid artery reendothelialization after perivascular electric injury were compared in wild-type, human ApoE3-expressing, and ApoE4-expressing mice. The third aim is to determine the role of endothelial cell ApoER2 in atheroprotection. We have successfully created floxed ApoER2 mice, and atherosclerosis development will be evaluated in crosses of ApoER2flox/flox with endothelial cell-expressing Cre and LDLR-/- mice in the future. From the unique perspective of apolipoprotein signaling in endothelium, the proposed work will enhance our fundamental understanding of ApoE and ApoER2 in cardiovascular health and disease.
Apolipoproteins E, Cardiovascular Diseases, Endothelial Cells
University of Texas Southwestern Medical Center
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