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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 18, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm107
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Heme Oxygenase Promotes Progenitor Cell Mobilization, Neovascularization, and Functional Recovery after Critical Hind-Limb Ischemia in Mice

Jörn Tongers, Julia-Marie Knapp, Mortimer Korf, Tibor Kempf, Anne Limbourg, Florian P. Limbourg, Zhixoing Li, Daniela Fraccarollo, Johann Bauersachs, Xiaoqiang Han, Helmut Drexler, Beate Fiedler and Kai C. Wollert

Dept. of Cardiology and Angiology, Hannover University Medical School, 30625 Hannover, Germany (J.T., J.M.K., M.K., T.K., A.L., F.L., H.D., B.F., K.C.W.)
Dept. of Experimental Hematology, Hannover University Medical School, 30625 Hannover, Germany (Z.L.)
Department of Medicine, University of Würzburg, 97080 Würzburg, Germany (D.F., J.B.)
Dept. of Pathology, Northwestern University, 60611 Chicago, Illinois (X.H.)

Address for correspondence: Prof. Dr. Kai C. Wollert Abt. Kardiologie und Angiologie Medizinische Hochschule Hannover Carl-Neuberg Str. 1 30625 Hannover, Germany phone: +49 (511) 532-4055; fax: +49 (511) 532-5412 e-mail: wollert.kai{at}mh-hannover.de

Aim: Neovascularization is an important element of long-term functional recovery during chronic ischemia. We postulated that heme oxygenase (HO) is required for progenitor cell recruitment, neovascularization, and blood flow recovery after critical hind-limb ischemia.

Methods: The femoral artery was ligated in FVB/N mice proximal to its superficial and deep branches. Blood flow in the ischemic hind-limb was determined by laser Doppler perfusion imaging. Capillary density was measured by isolectin staining, and mobilization of Sca-1+/Kdr+ progenitor cells by FACS analysis. Progenitor cell recruitment to the ischemic hind-limb was assessed after Tie2-lacZ transgenic bone marrow transplantation.

Results: Blood flow recovery after femoral artery ligation was significantly blunted in mice treated with the HO inhibitor tin protoporphyrin-IX (25 mg/kg i.p., every other day). HO-inhibited mice developed more pronounced limb necrosis, associated with impaired hind-limb motor function. Capillary density in the ischemic hind-limb and mobilization of Sca-1+/Kdr+ progenitor cells were significantly reduced after HO inhibition. After transplantation of Tie2-lacZ transgenic bone marrow cells into lethally irradiated wild-type mice, fewer LacZ+ cells were detected in the ischemic hind-limb muscle of HO-inhibited mice. Mechanistically, HO inhibition prevented the establishment of a stromal cell-derived factor-1 gradient for progenitor cell mobilization between the ischemic hind-limb and bone marrow.

Conclusions: Heme oxygenases are required for progenitor cell recruitment, neovascularization, and functional recovery after hind-limb ischemia.

Time for primary review: 20


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