Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis

Yun He

Yan Luo

Shibo Tang

Iiro Rajantie

Xianghong Li+8 authors

^{Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut, USA.}^{School of Public Health, and}^{Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China.}^{Molecular and Cancer Biology Program and Ludwig Institute for Cancer Research, Haartman Institute, Biomedicum Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland.}^{Department of Experimental Cardiology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.}^{Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), Leuven, Belgium.}

Address correspondence to: Wang Min, Interdepartmental Program in Vascular Biology and Transplantation, Department of Pathology, Yale University School of Medicine, BCMM 454, 295 Congress Avenue, New Haven, Connecticut 06510, USA. Phone: (203) 785-6047; Fax: (203) 737-2293; E-mail: ude.elay@nim.gnaw .

Received 2006 Feb 6; Accepted 2006 Jun 27.

Abstract

Bmx/Etk non-receptor tyrosine protein kinase has been implicated in endothelial cell migration and tube formation in vitro. However, the role of Bmx in vivo is not known. Bmx is highly induced in the vasculature of ischemic hind limbs. We used both mice with a genetic deletion of Bmx (Bmx-KO mice) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg mice) to study the role of Bmx in ischemia-mediated arteriogenesis/angiogenesis. In response to ischemia, Bmx-KO mice had markedly reduced, whereas Bmx-SK-Tg mice had enhanced, clinical recovery, limb perfusion, and ischemic reserve capacity when compared with nontransgenic control mice. The functional outcomes in these mice were correlated with ischemia-initiated arteriogenesis, capillary formation, and vessel maturation as well as Bmx-dependent expression/activation of TNF receptor 2– and VEGFR2-mediated (TNFR2/VEGFR2-mediated) angiogenic signaling in both hind limb and bone marrow. More importantly, results of bone marrow transplantation studies showed that Bmx in bone marrow–derived cells plays a critical role in the early phase of ischemic tissue remodeling. Our study provides the first demonstration to our knowledge that Bmx in endothelium and bone marrow plays a critical role in arteriogenesis/angiogenesis in vivo and suggests that Bmx may be a novel target for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease.

Abstract

Acknowledgments

This work was supported in part by an Established Investigator Award from the American Heart Association and NIH grant R01HL65978-5 to W. Min and grants from the “973” National Basic Key Research and Development Program and the National Natural Science Foundation of China to Y. He. We thank Wawrzyniec L. Dobrucki for assistance on the microCT analysis.

Acknowledgments

Footnotes

Nonstandard abbreviations used: BMT, bone marrow transplantation; Bmx, bone marrow tyrosine kinase in chromosome X; EPC, endothelial progenitor cell; PH, pleckstrin homology; PlGF, placental growth factor; qRT-PCR, real-time quantitative PCR; TNFR, TNF receptor.

Conflict of interest: The authors have declared that no conflict of interest exists.

Citation for this article:J. Clin. Invest.116:2344–2355 (2006). doi:10.1172/JCI28123.

Yun He and Yan Luo contributed equally to this work.

Footnotes

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