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Arterioscler Thromb Vasc Biol. 2017 May;37(5):794-803. doi: 10.1161/ATVBAHA.117.309284. Epub 2017 Mar 30.

VEGF-A Regulates Cellular Localization of SR-BI as Well as Transendothelial Transport of HDL but Not LDL.

Author information

1
From the Institute of Clinical Chemistry, University and University Hospital of Zurich, Schlieren, Switzerland (S.V., M.Y., A.P., D.P., P.Z., L.R., A.v.E.); Competence Center for Integrated Human Physiology, University of Zurich, Switzerland (S.V., M.Y., D.P., P.Z., L.R., A.v.E.); Department of Pharmacy, University of Parma, Italy (A.P.); and Scientific Center for Optical and Electron Microscopy, ETH Zurich, Switzerland (R.M., S.F.N., A.R., M.S., S.S.).
2
From the Institute of Clinical Chemistry, University and University Hospital of Zurich, Schlieren, Switzerland (S.V., M.Y., A.P., D.P., P.Z., L.R., A.v.E.); Competence Center for Integrated Human Physiology, University of Zurich, Switzerland (S.V., M.Y., D.P., P.Z., L.R., A.v.E.); Department of Pharmacy, University of Parma, Italy (A.P.); and Scientific Center for Optical and Electron Microscopy, ETH Zurich, Switzerland (R.M., S.F.N., A.R., M.S., S.S.). arnold.voneckardstein@usz.ch lucia.rohrer@usz.ch.

Abstract

OBJECTIVE:

Low- and high-density lipoproteins (LDL and HDL) must pass the endothelial layer to exert pro- and antiatherogenic activities, respectively, within the vascular wall. However, the rate-limiting factors that mediate transendothelial transport of lipoproteins are yet little known. Therefore, we performed a high-throughput screen with kinase drug inhibitors to identify modulators of transendothelial LDL and HDL transport.

APPROACH AND RESULTS:

Microscopy-based high-content screening was performed by incubating human aortic endothelial cells with 141 kinase-inhibiting drugs and fluorescent-labeled LDL or HDL. Inhibitors of vascular endothelial growth factor (VEGF) receptors (VEGFR) significantly decreased the uptake of HDL but not LDL. Silencing of VEGF receptor 2 significantly decreased cellular binding, association, and transendothelial transport of 125I-HDL but not 125I-LDL. RNA interference with VEGF receptor 1 or VEGF receptor 3 had no effect. Binding, uptake, and transport of HDL but not LDL were strongly reduced in the absence of VEGF-A from the cell culture medium and were restored by the addition of VEGF-A. The restoring effect of VEGF-A on endothelial binding, uptake, and transport of HDL was abrogated by pharmacological inhibition of phosphatidyl-inositol 3 kinase/protein kinase B or p38 mitogen-activated protein kinase, as well as silencing of scavenger receptor BI. Moreover, the presence of VEGF-A was found to be a prerequisite for the localization of scavenger receptor BI in the plasma membrane of endothelial cells.

CONCLUSIONS:

The identification of VEGF as a regulatory factor of transendothelial transport of HDL but not LDL supports the concept that the endothelium is a specific and, hence, druggable barrier for the entry of lipoproteins into the vascular wall.

KEYWORDS:

HDL; SR-BI; VEGF-A; atherosclerosis; endothelial cells

PMID:
28360088
DOI:
10.1161/ATVBAHA.117.309284
[Indexed for MEDLINE]
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