Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis
Open Access
- 24 August 2006
- journal article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 116 (9) , 2344-2355
- https://doi.org/10.1172/jci28123
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.Keywords
This publication has 46 references indexed in Scilit:
- VEGF Receptor Signal TransductionScience's STKE, 2001
- Bmx Tyrosine Kinase Has a Redundant Function Downstream of Angiopoietin and Vascular Endothelial Growth Factor Receptors in Arterial EndotheliumMolecular and Cellular Biology, 2001
- Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditionsNature Medicine, 2001
- Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domainNature Cell Biology, 2001
- VEGF-Induced Activation of Phosphoinositide 3-Kinase Is Dependent on Focal Adhesion KinaseExperimental Cell Research, 2001
- Signaling network of the Btk family kinasesOncogene, 2000
- Antiangiogenic Effect of Interleukin-10 in Ischemia-Induced Angiogenesis in Mice HindlimbCirculation Research, 2000
- The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.Nature Medicine, 2000
- A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3′-kinase activation and endothelial cell migrationThe EMBO Journal, 2000
- Etk, a Btk Family Tyrosine Kinase, Mediates Cellular Transformation by Linking Src to STAT3 ActivationMolecular and Cellular Biology, 2000