Involvement of E-selectin in recruitment of endothelial progenitor cells and angiogenesis in ischemic muscle.
E-selectin plays critical roles in tethering leukocytes to endothelial cells (ECs). We studied the role of E-selectin in endothelial progenitor cell (EPC) homing and vasculogenesis. After ischemia, the expression of E-selectin on ECs peaked 6 to 12 hours and returned to baseline at 24 hours, whereas the level of soluble E-selectin (sE-selectin) in serum increased over 24 hours and remained high at day 7. Mouse bone marrow-derived EPCs expressed not only E-selectin but also its ligand. Homing of circulating EPCs to ischemic limb was significantly impaired in E-selectin knock-out mice, as well as wild-type mice pretreated with blocking antibody against E-selectin, which was rescued by local sE-selectin injection. Mechanism for this is that sE-selectin stimulated not only ECs to express ICAM-1, but also EPCs to secrete interleukin-8 (IL-8), leading to enhanced migration and incorporation to ECs capillary formation. In therapeutic aspect, local treatment with sE-selectin enhanced efficacy of EPC transplantation for vasculogenesis and salvage of ischemic limb. Conversely, when E-selectin was knocked down by E-selectin small interfering RNA, blood flow recovery after EPC transplantation was significantly impaired. But this impaired vasculogenesis was rescued by sE-selectin. In conclusion, these data demonstrate E-selectin is a pivotal molecule for EPCs' homing to ischemic limb and vasculogenesis.
Oh
Il-Young
IY
Department of Internal Medicine, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
Yoon
Chang-Hwan
CH
Hur
Jin
J
Kim
Ji-Hyun
JH
Kim
Tae-Youn
TY
Lee
Choon-Soo
CS
Park
Kyung-Woo
KW
Chae
In-Ho
IH
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D000818:Animals; D002465:Cell Movement; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016209:Interleukin-8 / Q000096:biosynthesis; D007511:Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D033581:Stem Cell Transplantation; D013234:Stem Cells; D013997:Time Factors; D014184:Transplantation, Homologous
D019040:E-Selectin; D016209:Interleukin-8; D034741:RNA, Small Interfering