Published Online
on February 21, 2005

A more recent version of this article appeared on March 8, 2005

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Submitted on September 7, 2004
Revised on November 2, 2004
Accepted on November 10, 2004

Endothelial Progenitor Cells Are Rapidly Recruited to Myocardium and Mediate Protective Effect of Ischemic Preconditioning via "Imported" Nitric Oxide Synthase Activity

Masaaki Ii MD, PhD, Hiromi Nishimura MD, PhD, Atsushi Iwakura MD, PhD, Andrea Wecker BS, Elizabeth Eaton BS, Takayuki Asahara MD, PhD, and Douglas W. Losordo MD^*

From the Division of Cardiovascular Research (M.I., A.I., A.W., E.E., D.W.L.), Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass, and Regenerative Medicine (H.N., T.A.), Institute of Biomedical Research and Innovation, Kobe, Japan.

^* To whom correspondence should be addressed. E-mail: douglas.losordo{at}tufts.edu.

Background--The function of bone marrow-derived endothelial progenitor cells (EPCs) in repair of ischemic tissue has been the subject of intense scrutiny, and the capacity of these cells to contribute significantly to new blood vessels remains controversial. The possibility that EPCs could act as reservoirs of cytokines has been implied by several observations; however, a specific role for cytokine delivery has not been identified.

Methods and Results--We performed a series of experiments that revealed the rapid recruitment of EPCs to the myocardium by very short periods of ischemia, so-called ischemic preconditioning. The recruited EPCs express an array of potentially cardioprotective cytokines including nitric oxide synthase isoforms. Bone marrow transplantation studies, using donor marrow null for nitric oxide synthase isoforms, revealed that both endothelial and inducible nitric oxide synthase derived from bone marrow cells play essential roles in the cardioprotective effect that normally occurs after ischemic preconditioning.

Conclusions--These findings provide novel insights about the role of bone marrow-derived cells in ischemic preconditioning and also reveal that distinct mechanisms regulate recovery after ischemia-reperfusion and chronic ischemic injury.

Key words: myocardial infarction • ischemia • nitric oxide synthase • blood cells

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