on December 14, 2006
Published online before print December 14, 2006, doi: 10.1161/01.ATV.0000254812.23238.2b
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Submitted on August 13, 2006
Accepted on November 13, 2006
Endothelial E-Selectin Potentiates Neovascularization via Endothelial Progenitor Cell-Dependent and -Independent Mechanisms
Yasunobu Nishiwaki ;
From Department of Cardiovascular Medicine (Y.N., M.I.), Tokyo Medical and Dental University, School of Medicine, Tokyo, Japan; Department of Medical Biochemistry (Y.N., M.Y., N.N.), Tokyo Medical and Dental University, School of Medicine, Tokyo, Japan; Department of Regenerative Medicine (H.I., H.M., T.A.), Tokai University, School of Medicine, Kanagawa, Japan.
* To whom correspondence should be addressed. E-mail: masavasc{at}tmd.ac.jp.
Background-- Although potential participation of bone marrow-derived circulating endothelial progenitor cells (EPCs) to neoangiogenesis has been proposed, the precise molecular mechanisms of EPC recruitment to vascular endothelium has not been fully elucidated.
Methods and Results-- Peripheral blood mononuclear cells were isolated from healthy volunteers and cultured for 7 days to obtain EPCs. Tumor necrosis factor-
-activated human umbilical vein endothelial cells (HUVECs) supported significantly more rolling and adhesion of EPCs compared with inactivated HUVEC monolayer. Pretreatment of activated HUVEC with an adhesion-blocking mAb to E-selectin significantly reduced EPCs adhesion to HUVECs. When HUVECs were transduced with a recombinant adenovirus of E-selectin (AdRSVE-sel) or that of 
-galactosidase (AdRSVLacZ), E-selectin-transduced but not LacZ-transduced HUVECs exhibited significantly more EPC rolling as well as adhesion. Further, effect of AdRSVE-sel or AdRSVLacZ was examined in mouse hind limb ischemic model. AdRSVE-sel-transduced mice showed significantly less limb necrosis and higher laser Doppler ratio when compared with AdRSVLacZ-transduced mice. Interestingly, blood flow recovery of ischemic limb observed in AdRSVE-sel-transduced mice was more prominent when combined with EPC administration compared with that of AdRSVLacZ-transduced mice.
Conclusions--Endothelial E-selectin plays a crucial role in EPC-endothelial interaction in vitro. The importance of E-selectin was also confirmed in vivo even in the absence of exogenous EPC. These data provide molecular background for novel cell-based therapy for ischemic atherosclerosis.
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