Abstract
Background: The present study explored the effect of endothelial nitric oxide synthase (eNOS) gene transfer on the angiogenic potential of ex vivo expanded endothelial progenitor cells (EPCs) in a rabbit model of hindlimb ischemia. Methods: Rabbit peripheral blood EPCs were cultured and transfected with mammalian expression vector pcDNA3.1-eNOS containing full-length human eNOS gene. Ischemia was induced in the right hind limb of three groups of rabbits by ligation of the distal external iliac artery and excision of the common and superficial femoral arteries. In one group of animals, ten days after the surgery, autologous eNOS-EPCs were transplanted intramuscularly in the ischemic limb. Two other groups received an equivalent number of unmodified EPCs or phosphate buffered saline (PBS) respectively. Results: Two weeks after cell transplantation, the in vivo expression of eNOS was detected in limb tissue sections of eNOS-EPCs treated animals. Animals treated with eNOS-EPCs had a significant reduction in ischemic muscle necrosis and inflammation, augmentation in the capillary density (P< 0.05) and angiographic scores demonstrating distal arterial reconstitution and enhanced angiogenesis in comparison to animals transplanted with EPCs or PBS (P< 0.05). Conclusion: We conclude that modification of EPCs by eNOS constitutes an effective strategy to improve the efficacy of EPCs for therapeutic angiogenesis.
Highlights
Therapeutic angiogenesis represents an innovative strategy to treat vascular insufficiency
In our previous in vitro study, we demonstrated enhanced migration, differentiation and angiogenic potential of endothelial progenitor cells (EPCs) over expressing endothelial nitric oxide synthase (eNOS) [18]
In the present study, we further evaluated the efficacy of genetically modified autologous EPCs over expressing eNOS vis-à-vis unmodified EPCs in inducing angiogenesis in a rabbit model of experimentally induced hind limb ischemia
Summary
Therapeutic angiogenesis represents an innovative strategy to treat vascular insufficiency. It is aimed at improving the compensatory mechanisms of angiogenesis and arteriogenesis by stimulating the growth and development of collateral vessels in critical peripheral or myocardial ischemia. Bone marrow-derived endothelial progenitor cells (EPCs) harvested from peripheral blood have been recently identified for their contribution to angiogenesis and revascularization of ischemic tissues [1]. EPCs proliferate and migrate in response to angiogenic growth factors and differentiate into mature endothelial cells in situ for blood vessel formation [2]. The present study explored the effect of endothelial nitric oxide synthase (eNOS) gene transfer on the angiogenic potential of ex vivo expanded endothelial progenitor cells (EPCs) in a rabbit model of hindlimb ischemia
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