期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2011
卷号：108
期号：23
页码：9613-9618
DOI：10.1073/pnas.1103187108
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM+ HDL contained S1P, whereas ApoM- HDL did not. Moreover, HDL in Apom-/- mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-A structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM+ HDL induced S1P1 receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM- HDL did not. Importantly, lack of S1P in the HDL fraction of Apom-/- mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P1 receptor on endothelial cells, is a vasculoprotective constituent of HDL.
