Oxidized low density lipoprotein impairs endothelial progenitor cell function by downregulation of E-selectin and integrin alpha(v)beta5.
BACKGROUND
Oxidized low density lipoprotein (oxLDL) has been shown to induce apoptosis and senescence of endothelial progenitor cells (EPC). In the present study, we hypothesized that even sub-apoptotic concentrations of oxLDL impair the angiogenic potential of EPC and investigated if this effect is mediated by affecting adhesion and incorporation.


METHODS
A co-culture system of human microvascular endothelial cells and EPC was used to study the effect of sub-apoptotic concentrations of native (nLDL) and oxLDL on cell-cell interaction. The expression and the functional role of angiogenic adhesion molecules and integrins was monitored by FACS and neutralizing assay, respectively.


RESULTS
We observed an inhibition of tube formation and impairment of EPC integration into the vascular network of mature endothelial cells by oxLDL. In contrast, nLDL did not affect angiogenic properties of EPC. Incubation of EPC with sub-apoptotic oxLDL concentrations significantly decreased E-selectin and integrin alpha(v)beta(5) expression (37.6% positive events vs. 71.5% and 24.3% vs. 49.9% compared to control culture media without oxLDL). Interestingly, expression of alpha(v)beta(3), VE-cadherin and CD31 remained unchanged. Blocking of E-selectin and integrin alpha(v)beta(5) by neutralizing antibody effectively inhibited adhesion of EPC to differentiated endothelial cells (56.5% and 41.9% of control; p<0.001).


CONCLUSIONS
In conclusion, oxidative alteration of LDL impairs angiogenic properties of EPC at sub-apoptotic levels by downregulation of E-selectin and integrin alpha(v)beta(5), both substantial mediators of EPC-endothelial cell interaction.
Di Santo
Stefano
S
Department of Vascular Medicine, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, CH-3010 Bern, Switzerland.
Diehm
Nicolas
N
Ortmann
Jana
J
Völzmann
Jan
J
Yang
Zijiang
Z
Keo
Hong-Hak
HH
Baumgartner
Iris
I
Kalka
Christoph
C
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D015536:Down-Regulation; D004338:Drug Combinations; D019040:E-Selectin / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011509:Proteoglycans / Q000737:chemistry; D019030:Receptors, Vitronectin / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000906:Antibodies; D004338:Drug Combinations; D019040:E-Selectin; D007797:Laminin; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C099252:oxidized low density lipoprotein; C059485:matrigel; D003094:Collagen