Impairment of human cell-based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with L-arginine supplementation.
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.
Suuronen
Erik J
EJ
Division of Cardiac Surgery, University of Ottawa, Ottawa, Ontario, Canada.
Hazra
Samir
S
Zhang
Pingchuan
P
Vincent
Renaud
R
Kumarathasan
Premkumari
P
Zhang
Yan
Y
Price
Joel
J
Chan
Vincent
V
Sellke
Frank W
FW
Mesana
Thierry G
TG
Veinot
John P
JP
Ruel
Marc
M
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
D016207:Cytokines; D019332:Endothelin-1; D009573:Nitrites; D001120:Arginine