Abstract 3374: Critical Function Of Bmx/etk In Ischemia-mediated Arteriogenesis And Angiogenesis
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. We use both mice with a genetic deletion of Bmx (Bmx-KO) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg) to study the role of Bmx in several mouse angiogeneisis models including ischemic hindlimb, retina and tumor angiogenesis models. Bmx is highly induced in vasculature of ischemic hindlimb after femoral artery ligation, a commonly used arteriogenesis/angiogenesis model. In response to ischemia, Bmx-KO mice had a marked deficit whereas Bmx-SK-Tg mice had enhanced capacity in clinical recovery, limb perfusion and ischemic reserve capacity when compared to 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 TNFR2 and VEGFR2-angiogenic signaling in both hindlimb and bone marrow. Similar results were obtained from retina and tumor models. More importantly, bone marrow transplantation 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 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.
This work is supported by AHA EIA award (2004 –2008) to WM.
This research has received full or partial funding support from the American Heart Association, AHA National Center.