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PRECLINICAL STUDIES

A Relationship Between Vascular Endothelial Growth Factor, Angiogenesis, and Cardiac Repair After Muscle Stem Cell Transplantation Into Ischemic Hearts

Thomas R. Payne, PhD^_*,,, Hideki Oshima, MD, PhD^_*,, Masaho Okada, MD^_*,, Nobuo Momoi, MD, Kimimasa Tobita, MD, Bradley B. Keller, MD, Hairong Peng, MD, PhD^_*, and Johnny Huard, PhD^_*,,,||,_*

^_* Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Pediatric Cardiovascular Research Program, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania,
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
^|| Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania

Manuscript received January 5, 2007; revised manuscript received April 3, 2007, accepted April 22, 2007.

^_* Reprint requests and correspondence: Dr. Johnny Huard, 3705 5th Avenue, 4100 Rangos Research Center, Pittsburgh, Pennsylvania 15213. (Email: jhuard{at}pitt.edu).

Objectives: We investigated whether vascular endothelial growth factor (VEGF) was associated with the angiogenic and therapeutic effects induced after transplantation of skeletal muscle-derived stem cells (MDSCs) into a myocardial infarction (MI).

Background: Because very few MDSCs were found to differentiate into new blood vessels when injected into the heart, the mechanism underlying the occurrence of angiogenesis after MDSC transplantation is currently unknown. In the present study, we used a gain- or loss-of-VEGF function approach with skeletal MDSCs engineered to express VEGF or soluble Flt1, a VEGF-specific antagonist, to identify the involvement of VEGF in MDSC transplantation-induced neoangiogenesis.

Methods: Vascular endothelial growth factor- and soluble Flt1-engineered MDSCs were injected into an acute MI. Angiogenesis and cardiac function were evaluated by immunohistochemistry and echocardiography.

Results: Both control and VEGF-overexpressing MDSCs induced angiogenesis, prevented adverse cardiac remodeling, and improved function compared with saline-injected hearts. However, these therapeutic effects were diminished in hearts transplanted with MDSCs expressing soluble Flt1 despite successful cell engraftment. In vitro experiments demonstrated that MDSCs increased secretion of VEGF in response to hypoxia and cyclic stretch (likely conditions in ischemic hearts), suggesting that transplanted MDSCs release VEGF in vivo.

Conclusions: Our findings suggest that VEGF is essential for the induction of angiogenesis and functional improvements observed after MDSC transplantation for infarct repair.

Abbreviations and Acronyms   FS = fractional shortening   fskMyHC = fast skeletal myosin heavy chain   LV = left ventricle/ventricular   MDSC = muscle-derived stem cell   MI = myocardial infarction   nLacZ = nuclear-localized LacZ   PBS = phosphate-buffered saline   sFlt1 = soluble Flt1   VEGF = vascular endothelial growth factor

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