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(Circulation. 2004;110:1398-1405.)
© 2004 American Heart Association, Inc.

Original Articles

Synergistic Effect of Bone Marrow Mobilization and Vascular Endothelial Growth Factor-2 Gene Therapy in Myocardial Ischemia

Atsuhiko Kawamoto, MD PhD^*; Toshinori Murayama, MD PhD^*; Kengo Kusano, MD PhD; Masaaki Ii, MD PhD; Tengiz Tkebuchava, MD; Satoshi Shintani, MD PhD; Atsushi Iwakura, MD PhD; Ingrid Johnson, BS; Patrick von Samson, MD; Allison Hanley, BS; Mary Gavin, BS; Cindy Curry, BS; Marcy Silver, BS; Hong Ma, BS; Marianne Kearney, BS; Douglas W. Losordo, MD

From the Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass.

Correspondence to Douglas W. Losordo, MD, Division of Cardiovascular Research, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu

Received November 11, 2003; de novo received March 16, 2004; revision received June 8, 2004; accepted June 14, 2004.

Background— We performed a series of investigations to test the hypothesis that combining angiogenic gene therapy and cytokine (CK)-induced endothelial progenitor cell mobilization would be superior to either strategy alone for treatment of chronic myocardial ischemia.

Methods and Results— A swine model of chronic myocardial ischemia and a murine model of acute myocardial infarction were used in this study. In both models, animals were randomly assigned to 1 of 4 treatment groups: Combo group, intramyocardial vascular endothelial growth factor (VEGF)-2 gene transfer plus subcutaneous injection of CKs; VEGF-2, VEGF-2 gene transfer plus saline subcutaneously injected; CK, empty vector transfer plus CKs; and control, empty vector plus subcutaneous saline. Acute myocardial infarction was also induced in wild-type mice 4 weeks after bone marrow transplantation from enhanced green fluorescent protein transgenic mice to permit observation of bone marrow–derived cells in the myocardium after acute myocardial infarction. In chronic myocardial ischemia, combination therapy resulted in superior improvement in all indexes of perfusion and function compared with all other treatment groups. In the bone marrow transplant mice, double immunofluorescent staining revealed that the combination of CK-induced mobilization and local VEGF-2 gene transfer resulted in a significant increase in the number of bone marrow–derived cells incorporating into the neovasculature, indicating that recruitment and/or retention of bone marrow–derived progenitors was enhanced by mobilization and that local VEGF-2 gene transfer can provide signals for recruitment or incorporation of circulating progenitor cells.

Conclusions— Mobilization of endothelial progenitor cells with cytokines potentiates VEGF-2 gene therapy for myocardial ischemia and enhances bone marrow cell incorporation into ischemic myocardium.

Key Words: cytokines • endothelial cells • ischemia • stem cells • vascular endothelial growth factor

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