title: Impairment of human cell-based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with L-arginine supplementation.
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 x 10(6) 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 < or = .004). Lower arteriolar densities were found in groups and B and D than in groups A and C (P < or = .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.
authors.affiliation: Division of Cardiac Surgery, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
authors.forename: Samir
authors.initials: S
authors.lastname: Hazra
authors.forename: Pingchuan
authors.initials: P
authors.lastname: Zhang
authors.forename: Renaud
authors.initials: R
authors.lastname: Vincent
authors.forename: Premkumari
authors.initials: P
authors.lastname: Kumarathasan
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Joel
authors.initials: J
authors.lastname: Price
authors.forename: Vincent
authors.initials: V
authors.lastname: Chan
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
authors.forename: Thierry G
authors.initials: TG
authors.lastname: Mesana
authors.forename: John P
authors.initials: JP
authors.lastname: Veinot
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D042783:Endothelial Cells / Q000502:physiology* / Q000637:transplantation; D019332:Endothelin-1 / Q000097:blood; D005121:Extremities / Q000098:blood supply; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009573:Nitrites / Q000097:blood; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D019332:Endothelin-1; D009573:Nitrites; D001120:Arginine