Impairment of human cell–based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with l-arginine supplementation
Received 23 July 2008; received in revised form 10 April 2009; accepted 23 April 2009.
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 × 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.
aDivision of Cardiac Surgery, University of Ottawa, Ottawa, Ontario, Canada
bDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
cDepartment of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
dHealthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
eDivision of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Mass
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.
Supported by grant MOP-77536 from the Canadian Institutes of Health Research (to M.R. and E.J.S.) and by grant NA5905 from the Heart & Stroke Foundation of Canada (to M.R.).
ABSTRACT