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J Thorac Cardiovasc Surg 2010;139:209-216
© 2010 The American Association for Thoracic Surgery

Evolving Technology/Basic Science

Impairment of human cell–based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with L-arginine supplementation

^a Division of Cardiac Surgery, University of Ottawa, Ottawa, Ontario, Canada
^b Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
^c Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
^d Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
^e Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Mass

Received for publication July 23, 2008; revisions received April 10, 2009; accepted for publication April 23, 2009.

^_* Address for reprints: Marc Ruel, MD, MPH, University of Ottawa Heart Institute, Division of Cardiac Surgery, 40 Ruskin St, Laboratory H5227, Ottawa, Ontario, Canada, K1Y 4W7. (Email: mruel{at}ottawaheart.ca).

Objective: Clinical efficacy of cardiac cell therapy may be compromised by its target population, patients with endothelial dysfunction. In vivo inhibition by endothelial dysfunction has been demonstrated for protein angiogenesis but remains unclear for cell therapy. We examined whether hypercholesterolemia inhibits vasculogenic effects of transplanted human circulating progenitor cells in ischemic tissue and whether L-arginine, a nitric oxide donor, might prevent impairment.

Methods: Athymic rats were fed either normal (group A) or high-cholesterol diets, the latter without (group B) or with (group C) oral L-arginine supplementation. Two weeks later, these rats underwent left femoral artery ligation followed by injection of 2 x 10⁶ human circulating progenitor cells into left hind-limb muscle. A fourth group (group D) received supplemented high-cholesterol diets but no cells.

Results: Group B had biochemical evidence of endothelial dysfunction and reduced tissue endothelial nitric oxide synthase expression, whereas group A levels were the same as in group C. By 21 postoperative days, left hind-limb perfusion had recovered fully in groups A and C, partially in D, and not at all in B (38% lower than group A, P .004). Lower arteriolar densities were found in groups and B and D than in groups A and C (P .02). Engrafted human cell numbers were equivalent in all cell-transplanted groups after 3 weeks.

Conclusions: Endothelial dysfunction inhibited effects of cell therapy, specifically vasculogenesis, suggesting a role for substrate modification to overcome this inhibition. Involved mechanisms appear related to use of cells but not engraftment and require further investigation.

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