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(Circulation Research. 2006;98:897.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Cardiac Ischemia Activates Vascular Endothelial Cadherin Promoter in Both Preexisting Vascular Cells and Bone Marrow Cells Involved in Neovascularization

Naoko Kogata, Yuji Arai, James T. Pearson, Kazuaki Hashimoto, Kyoko Hidaka, Tatsuya Koyama, Satoshi Somekawa, Yoshikazu Nakaoka, Minetaro Ogawa, Ralf H. Adams, Masato Okada, Naoki Mochizuki

From the Departments of Structural Analysis (N.K., Y.N., T.K., S.S., N.M.), Bioscience (Y.A., K.H.), and Cardiac Physiology (J.T.P.); National Cardiovascular Center Research Institute, Osaka, Japan; the Department of Cell Differentiation, Institute for Molecular Embryology and Genetics (K.H., M.O.), Kumamoto University, Kumamoto, Japan; the Vascular Development Laboratory (R.H.A.), Cancer Research UK London Research Institute, United Kingdom; and the Department of Oncogene Research (M.O.), Institute for Microbial Disease, Osaka University, Japan.

Correspondence to Naoki Mochizuki, Department of Structural Analysis, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail nmochizu{at}ri.ncvc.go.jp

Vascular endothelial cadherin (VE-cadherin) is expressed on vascular endothelial cells, which are involved in developmental vessel formation. However, it remains elusive how VE-cadherin–expressing cells function in postnatal neovascularization. To trace VE-cadherin–expressing cells, we developed mice expressing either green fluorescent protein or LacZ driven by VE-cadherin promoter using Cre-loxP system. Although VE-cadherin promoter is less active after birth than during embryogenesis in blood vessels, it is reactivated on cardiac ischemia. Both types of reporter-positive cells are found in the vasculature and in the infarcted myocardium. Those found in the vasculature were pre-existing endothelial cells and incorporated endothelial progenitor cells derived from extracardiac tissue. In addition to the vasculature, VE-cadherin promoter-activated cells were positive for CD45 in the bone marrow cells of the infarcted mice. VE-cadherin promoter–reactivated CD45-positive leukocytes were also found in the infarcted area. In addition, VE-cadherin promoter was activated in the bone marrow vessels of the infarcted mice. Collectively, our findings reveal a new ischemia-induced neovascularization mechanism involving VE-cadherin; the re-expressed VE-cadherin–mediated cell adhesion between cells may be involved not only in homing of bone marrow–derived cells to ischemic area but also mobilization from bone marrow.

Key Words: vasculogenesis • angiogenesis • hemangioblast • ischemia • CD45

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