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

Erik J. Suuronen, Samir Hazra, Pingchuan Zhang, Renaud Vincent, Premkumari Kumarathasan, Yan Zhang, Joel Price, Vincent Chan, Frank W. Sellke, Thierry G. Mesana, John P. Veinot, Marc Ruel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)209-216.e2
JournalJournal of Thoracic and Cardiovascular Surgery
Volume139
Issue number1
DOIs
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Impairment of human cell-based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with l-arginine supplementation'. Together they form a unique fingerprint.

Cite this