Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury

Masaaki Ii, Hideya Takenaka, Jun Asai, Kayoko Ibusuki, Yusuke Mizukami, Kazuichi Maruyama, Youngsup Yoon, Andrea Wecker, Corinne Luedemann, Elizabeth Eaton, Marcy Silver, Tina Thorne, Douglas W. Losordo

Research output: Contribution to journalArticle

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Abstract

Delayed reendothelialization contributes to restenosis after angioplasty and stenting in diabetes. Prior data have shown that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to endothelial recovery after arterial injury. We investigated the hypothesis that the EPC contribution to reendothelialization may be impaired in diabetes, resulting in delayed reendothelialization. Reendothelialization was significantly reduced in diabetic mice compared with nondiabetic mice in a wire-induced carotid denudation model. The EPC contribution to neoendothelium was significantly reduced in Tie2/LacZ BM-transplanted diabetic versus nondiabetic mice. BM from diabetic and nondiabetic mice was transplanted into nondiabetic mice, revealing that reendothelialization was impaired in the recipients of diabetic BM. To examine the relative roles of denuded artery versus EPCs in diabetes, we injected diabetic and nondiabetic EPCs intravenously after arterial injury in diabetic and nondiabetic mice. Diabetic EPCs recruitment to the neoendothelium was significantly reduced, regardless of the diabetic status of the recipient mice. In vitro, diabetic EPCs exhibited decreased migration and adhesion activities. Vascular endothelial growth factor and endothelial NO synthase expressions were also significantly reduced in diabetic EPCs. Notably, thrombospondin-1 mRNA expression was significantly upregulated in diabetic EPCs, associating with the decreased EPC adhesion activity in vitro and in vivo. Reendothelialization is impaired by malfunctioning EPCs in diabetes. Diabetic EPCs have phenotypic differences involving thrombospondin-1 expression compared with nondiabetic EPCs, revealing potential novel mechanistic insights and therapeutic targets to improve reendothelialization and reduce restenosis in diabetes.

Original languageEnglish
Pages (from-to)697-704
Number of pages8
JournalCirculation Research
Volume98
Issue number5
DOIs
Publication statusPublished - 2006 Mar 1

Fingerprint

Thrombospondin 1
Wounds and Injuries
Bone Marrow
Endothelial Progenitor Cells
Angioplasty
Cell Adhesion
Nitric Oxide Synthase
Vascular Endothelial Growth Factor A

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Ii, Masaaki ; Takenaka, Hideya ; Asai, Jun ; Ibusuki, Kayoko ; Mizukami, Yusuke ; Maruyama, Kazuichi ; Yoon, Youngsup ; Wecker, Andrea ; Luedemann, Corinne ; Eaton, Elizabeth ; Silver, Marcy ; Thorne, Tina ; Losordo, Douglas W. / Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury. In: Circulation Research. 2006 ; Vol. 98, No. 5. pp. 697-704.
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abstract = "Delayed reendothelialization contributes to restenosis after angioplasty and stenting in diabetes. Prior data have shown that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to endothelial recovery after arterial injury. We investigated the hypothesis that the EPC contribution to reendothelialization may be impaired in diabetes, resulting in delayed reendothelialization. Reendothelialization was significantly reduced in diabetic mice compared with nondiabetic mice in a wire-induced carotid denudation model. The EPC contribution to neoendothelium was significantly reduced in Tie2/LacZ BM-transplanted diabetic versus nondiabetic mice. BM from diabetic and nondiabetic mice was transplanted into nondiabetic mice, revealing that reendothelialization was impaired in the recipients of diabetic BM. To examine the relative roles of denuded artery versus EPCs in diabetes, we injected diabetic and nondiabetic EPCs intravenously after arterial injury in diabetic and nondiabetic mice. Diabetic EPCs recruitment to the neoendothelium was significantly reduced, regardless of the diabetic status of the recipient mice. In vitro, diabetic EPCs exhibited decreased migration and adhesion activities. Vascular endothelial growth factor and endothelial NO synthase expressions were also significantly reduced in diabetic EPCs. Notably, thrombospondin-1 mRNA expression was significantly upregulated in diabetic EPCs, associating with the decreased EPC adhesion activity in vitro and in vivo. Reendothelialization is impaired by malfunctioning EPCs in diabetes. Diabetic EPCs have phenotypic differences involving thrombospondin-1 expression compared with nondiabetic EPCs, revealing potential novel mechanistic insights and therapeutic targets to improve reendothelialization and reduce restenosis in diabetes.",
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Ii, M, Takenaka, H, Asai, J, Ibusuki, K, Mizukami, Y, Maruyama, K, Yoon, Y, Wecker, A, Luedemann, C, Eaton, E, Silver, M, Thorne, T & Losordo, DW 2006, 'Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury', Circulation Research, vol. 98, no. 5, pp. 697-704. https://doi.org/10.1161/01.RES.0000209948.50943.ea

Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury. / Ii, Masaaki; Takenaka, Hideya; Asai, Jun; Ibusuki, Kayoko; Mizukami, Yusuke; Maruyama, Kazuichi; Yoon, Youngsup; Wecker, Andrea; Luedemann, Corinne; Eaton, Elizabeth; Silver, Marcy; Thorne, Tina; Losordo, Douglas W.

In: Circulation Research, Vol. 98, No. 5, 01.03.2006, p. 697-704.

Research output: Contribution to journalArticle

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T1 - Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury

AU - Ii, Masaaki

AU - Takenaka, Hideya

AU - Asai, Jun

AU - Ibusuki, Kayoko

AU - Mizukami, Yusuke

AU - Maruyama, Kazuichi

AU - Yoon, Youngsup

AU - Wecker, Andrea

AU - Luedemann, Corinne

AU - Eaton, Elizabeth

AU - Silver, Marcy

AU - Thorne, Tina

AU - Losordo, Douglas W.

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