Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis
Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis
复制标题
DOI：
10.1172/jci28123
复制
发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Min, Wang
中科院分区：
文献类型：
--
作者：
He, Yun;Luo, Yan;Min, Wang
Bmx/Etk非受体酪氨酸蛋白激酶在体外已被证实与内皮细胞迁移和管腔形成有关。然而，Bmx在体内的作用尚不清楚。Bmx在缺血后肢的脉管系统中高度诱导表达。我们使用了Bmx基因缺失的小鼠（Bmx - KO小鼠）以及在内皮Tie - 2增强子/启动子调控下表达组成性激活形式Bmx的转基因小鼠（Bmx - SK - Tg小鼠）来研究Bmx在缺血介导的动脉生成/血管生成中的作用。在缺血反应中，与非转基因对照小鼠相比，Bmx - KO小鼠的临床恢复、肢体灌注和缺血储备能力显著降低，而Bmx - SK - Tg小鼠则增强。这些小鼠的功能结果与缺血引发的动脉生成、毛细血管形成、血管成熟以及在后肢和骨髓中肿瘤坏死因子受体2（TNFR2）和血管内皮生长因子受体2（VEGFR2）介导的血管生成信号的Bmx依赖性表达/激活相关。更重要的是，骨髓移植研究结果表明，骨髓来源细胞中的Bmx在缺血组织重塑的早期阶段起着关键作用。我们的研究首次证明，据我们所知，内皮和骨髓中的Bmx在体内动脉生成/血管生成中起着关键作用，并提示Bmx可能是治疗冠状动脉疾病和外周动脉疾病等血管疾病的一个新靶点。
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.