Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury.
BACKGROUND
Carbon monoxide (CO) has emerged as a vascular homeostatic molecule that prevents balloon angioplasty-induced stenosis via antiproliferative effects on vascular smooth muscle cells. The effects of CO on reendothelialization have not been evaluated.


RESULTS
Exposure to CO has diametrically opposite effects on endothelial cell (EC) and vascular smooth muscle cell proliferation in rodent models of carotid injury. In contrast to its effect of blocking vascular smooth muscle cell growth, CO administered as a gas or as a CO-releasing molecule enhances proliferation and motility of ECs in vitro by >50% versus air controls, and in vivo, it accelerates reendothelialization of the denuded artery by day 4 after injury versus day 6 in air-treated animals. CO enhanced EC proliferation via rapid activation of RhoA (Ras homolog gene family, member A), followed by downstream phosphorylation of Akt, endothelial nitric oxide (NO) synthase phosphorylation, and a 60% increase in NO generation by ECs. CO drives cell cycle progression through phosphorylation of retinoblastoma, which is dependent in part on endothelial NO synthase-generated NO. Similarly, endothelial repair in vivo requires NO-dependent mobilization of bone marrow-derived EC progenitors, and CO yielded a 4-fold increase in the number of mobilized green fluorescent protein-Tie2-positive endothelial progenitor cells versus controls, with a corresponding accelerated deposition of differentiated green fluorescent protein-Tie2-positive ECs at the site of injury. CO was ineffective in augmenting EC repair and the ensuing development of intimal hyperplasia in eNOS(-/-) mice.


CONCLUSIONS
Collectively, the present data demonstrate that CO accelerates EC proliferation and vessel repair in a manner dependent on NO generation and enhanced recruitment of bone marrow-derived endothelial progenitor cells.
Wegiel
Barbara
B
Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Gallo
David J
DJ
Raman
Kathleen G
KG
Karlsson
Jenny M
JM
Ozanich
Brett
B
Chin
Beek Y
BY
Tzeng
Edith
E
Ahmad
Shakil
S
Ahmed
Asif
A
Baty
Catherine J
CJ
Otterbein
Leo E
LE
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002248:Carbon Monoxide / Q000378:metabolism*; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D016160:Retinoblastoma Protein; D009569:Nitric Oxide; D002248:Carbon Monoxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein