LDL induces cholesterol loading and inhibits endothelial proliferation and angiogenesis in Matrigels: correlation with impaired angiogenesis during wound healing

Hypercholesterolemia is a major risk factor for adverse cardiovascular outcomes, but its effect on angiogenesis and wound healing is not well understood. In this study, using a combination of mass spectrometry and laurdan two-photon imaging, we show that elevated levels of low-density lipoprotein (L...

Full description

Saved in:
Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2020-04, Vol.318 (4), p.C762-C776
Main Authors: Bogachkov, Yedida Y, Chen, Lin, Le Master, Elizabeth, Fancher, Ibra S, Zhao, Yan, Aguilar, Victor, Oh, Myung-Jin, Wary, Kishore K, DiPietro, Luisa A, Levitan, Irena
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Apolipoprotein E
Biopsy
Cardiovascular diseases
Cell adhesion & migration
Cell adhesion molecules
Cell cycle
Cell differentiation
Cell membranes
Cells, Cultured
Cholesterol
Cholesterol - metabolism
Collagen
Drug Combinations
Endothelial cells
Endothelial Cells - metabolism
Esters
Fibroblast growth factor 2
Growth factors
Hypercholesterolemia
Hypercholesterolemia - blood
Hypercholesterolemia - metabolism
Laminin
Lipoproteins, LDL - metabolism
Low density lipoprotein
Mass spectroscopy
Mice
Neovascularization, Pathologic - metabolism
Proteoglycans
Risk factors
S phase
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
Vascular endothelial growth factor receptors
Wound healing
Wound Healing - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Hypercholesterolemia is a major risk factor for adverse cardiovascular outcomes, but its effect on angiogenesis and wound healing is not well understood. In this study, using a combination of mass spectrometry and laurdan two-photon imaging, we show that elevated levels of low-density lipoprotein (LDL), like those seen in hypercholesterolemic patients, lead to an increase in both free cholesterol and cholesterol esters, as well as increase in lipid order of endothelial cell membranes. Notably, these effects are distinct and opposite to the lack of cholesterol loading and the disruption of lipid order observed in our earlier studies in response to oxidized LDL (oxLDL). The same pathological level of LDL leads to a significant inhibition of endothelial proliferation and cell cycle arrest in G2/M phase, whereas oxLDL enhances endothelial proliferation in S phase of the cycle. LDL but not oxLDL suppresses the expression of vascular endothelial growth factor receptor-2 while enhancing the expression of vascular endothelial growth factor (VEGF). Furthermore, we show that aged (8-10 mo) hypercholesterolemic apolipoprotein E-deficient (ApoE ) mice display delayed wound closure compared with age-matched C57/BL6 wild-type controls following a skin punch biopsy. The delay in wound healing is associated with a decreased expression of cluster of differentiation 31 platelet endothelial cell adhesion molecule endothelial marker and decreased angiogenesis within the wound bed. Furthermore, decreased endothelial responsiveness to the growth factors VEGF and basic fibroblast growth factor is observed in ApoE mice in Matrigel plugs and in Matrigels with high levels of LDL in wild-type mice. We propose that plasma hypercholesterolemia is antiangiogenic due to elevated levels of LDL.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00495.2018