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Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis
Yun He, … , Kari Alitalo, Wang Min
Yun He, … , Kari Alitalo, Wang Min
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2344-2355. https://doi.org/10.1172/JCI28123.
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Research Article Angiogenesis

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

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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.

Authors

Yun He, Yan Luo, Shibo Tang, Iiro Rajantie, Petri Salven, Matthias Heil, Rong Zhang, Dianhong Luo, Xianghong Li, Hongbo Chi, Jun Yu, Peter Carmeliet, Wolfgang Schaper, Albert J. Sinusas, William C. Sessa, Kari Alitalo, Wang Min

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Figure 7

Bmx in bone marrow–derived cells contributes to an early phase of ischemia-induced arteriogenesis/angiogenesis.

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Bmx in bone marrow–derived cells contributes to an early phase of ischem...
(A) Characterization of BMT. C57BL/6 mice were subjected to lethal irradiation followed by BMT by receiving bone marrow cells from WT (WT to WT), Bmx-KO mice (KO to WT), or Bmx-SK-Tg mice (Tg to WT). Success of BMT was controlled by genotyping of Bmx gene 6 weeks after BMT. The mice were then subjected to femoral artery ligation as described in Methods. Four weeks after ischemia, bone marrow was harvested, and expression of Bmx and Bmx-SK in BM was determined by Western blotting with anti-Bmx antibody. Bone marrow from WT and Bmx-SK-Tg mice without BMT/ligation was used as control. Expression of Bmx and Bmx-SK is indicated. Anti–β-tubulin antibody was used for normalization. (B) Pedal blood flow recovery after femoral artery ligation in C57BL/6 (WT Ctrl) versus mice that received bone marrow from WT (BMT of WT to WT), Bmx-KO mice (BMT of KO to WT), or Bmx-SK-Tg mice (BMT of Tg to WT). BMT was performed, and pedal blood flow recovery on indicated days after femoral artery ligation was assessed by laser Doppler imaging. *P < 0.05. (C) BMT of WT to Bmx-KO mice. Bmx-KO mice were subjected to lethal irradiation followed by BMT by receiving bone marrow cells from WT mice (WT to KO). Successful BMT was controlled by genotyping of the Bmx gene 6 weeks after BMT. The mice were then subjected to femoral artery ligation as described in Methods. WT and Bmx-KO mice without BMT were used as controls. Pedal blood flow recovery after femoral artery ligation was assessed by laser Doppler imaging. n = 10 for each strain. *P < 0.05.

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