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Cardiovascular Research Advance Access first published online on December 18, 2007
This version [Corrected Proof] published online on January 8, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm107
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Haeme oxygenase promotes progenitor cell mobilization, neovascularization, and functional recovery after critical hind-limb ischaemia in mice

Jörn Tongers1, Julia-Marie Knapp1, Mortimer Korf1, Tibor Kempf1, Anne Limbourg1, Florian P. Limbourg1, Zhixiong Li2, Daniela Fraccarollo3, Johann Bauersachs3, Xiaoqiang Han4, Helmut Drexler1, Beate Fiedler1 and Kai C. Wollert1,*

1 Department of Cardiology and Angiology, Hannover University Medical School, 30625 Hannover, Germany
2 Department of Experimental Hematology, Hannover University Medical School, 30625 Hannover, Germany
3 Department of Medicine, University of Würzburg, 97080 Würzburg, Germany
4 Department of Pathology, Northwestern University, Chicago, 60611 IL, USA

* Corresponding author. Tel: +49 511 532 4055; fax: +49 511 532 5412. E-mail address: wollert.kai{at}mh-hannover.de

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

Methods and results: The femoral artery was ligated in FVB/N mice proximal to its superficial and deep branches. Blood flow in the ischaemic 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 ischaemic hind-limb was assessed after Tie2-lacZ transgenic bone marrow transplantation. 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 ischaemic 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 ischaemic 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 ischaemic hind-limb and bone marrow.

Conclusion: HOs are required for progenitor cell recruitment, neovascularization, and functional recovery after HLI.

KEYWORDS Angiogenesis; Microcirculation; Regional blood flow

Time for primary review: 20 days


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