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Circulation

Year: 2010  |  Volume: 121  |  Issue: 9  |  Page No.: 1104 - 1112

Notch Signaling Regulates Endothelial Progenitor Cell Activity During Recovery From Arterial Injury in Hypercholesterolemic Mice

M Ii, K Takeshita, K Ibusuki, C Luedemann, A Wecker, E Eaton, T Thorne, T Asahara, J. K Liao and D. W. Losordo

Abstract

Background— Little is known about the role of endothelial progenitor cells (EPCs) in atherosclerosis. Accordingly, we performed a series of assessments with hypercholesterolemic (apolipoprotein E–null [ApoE–/–]) and wild-type (WT) mice to evaluate how cholesterol influences reendothelialization, atherosclerosis, and EPC function after arterial injury.

Methods and Results— Unexpectedly, reendothelialization (assessed by resistance to Evans blue staining) and circulating EPC counts (EPC culture assay) were greater in ApoE–/– mice than in WT mice, and transplantation of ApoE–/– bone marrow in WT mice accelerated endothelial recovery and increased recruitment of bone marrow–derived EPCs to the neoendothelium. Cholesterol concentration-dependently promoted the proliferation (MTS assay) of both ApoE–/– and WT EPCs, and the concentration dependence of EPC adhesion (to vitronectin-, collagen type I–, fibronectin-, and laminin-coated plates), migration (modified Boyden chamber assay), and antiapoptotic (terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling stain) activity was biphasic. Cholesterol enhanced the messenger RNA expression (quantitative, real-time reverse-transcription polymerase chain reaction) of vascular endothelial growth factor and inhibited Notch1 messenger RNA expression in both ApoE–/– and WT EPCs, whereas endothelial nitric oxide synthase messenger RNA expression increased in ApoE–/– EPCs and declined in WT EPCs after cholesterol exposure. EPC activity was greater in Notch1+/– EPCs than in WT EPCs, and transplantation of Notch1+/– bone marrow accelerated endothelial recovery after arterial injury in WT mice.

Conclusion— The results presented here provide novel insights into the role of EPCs during atherosclerosis and suggest that cholesterol and Notch1 may be involved in the regulation of EPC activity.

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