3.2 Ang-1/Tie-1的研究情况 研究表明Ang-1和Ang-4可以激活Tie-1,并且可以增加Ang-1、Ang-4与Tie-2的结合[15]。蛋白水解Tie-1的外功能区,然后激活pkc,产生能够传递信息的Tie-1受体。与Tie-2一样,Tie-1的激活可以通过PI-3k/akt途径增加内皮细胞的存活。Saharinen等[16]发现COMP-Ang1可以激活体外培养细胞Tie-1磷酸化。而且,Tie-1的激活可以通过Tie-2放大,并且比自身Ang-1/Ang-4诱导的激活更加有效。但是COMP-Ang1诱导的成年血管重建主要通过Tie-2而不是Tie-1。 Ets转录因子是调节血管生长的关键部位[17],通过激动受体分析,证明其中的一个序列(E-1)是激活培养细胞所必须的,选择性E-1三聚体可导致Tie-1激活的内皮细胞的显著抑制。鼠科动物Tie-1的启动子通过Ets-1、Ets-2、Elf-1和Nerf-2在体外转录,并且Ets序列突变会导致鼠类Tie-1启动子活性减弱[18]。Ets蛋白还是许多内皮相关基因的重要调节因素,包括血栓调解蛋白、vwf因子、ICAM-2、血管内皮钙粘蛋白、VEGF受体Flt-1。研究表明[19],删除E-2序列不会影响人类Tie-1启动子活性,E-1序列是保持体外Tie-1活性的最低要求。相似的,很多Ets结合部位在血管相关基因表达,包括Tie-2、血栓调节蛋白、ICAM-2和血管内皮钙粘蛋白,它们在血管内皮增殖、分化功能上起关键作用,这个途径也许会进一步扩大有关于肿瘤和病理上血管内皮增殖和功能紊乱疾病的治疗思路。
4 展望
随着研究的深入,发现很多疾病过程与血管的再生、渗透性增加或者血管功能异常引起的组织缺血缺氧有关,研究调节血管网的信号转导机制成为治疗这类疾病的一个有效途径。Ang-1/Tie系统在增加血管成熟性、减少新生血管生成、抑制渗漏、增加淋巴管形成促进组织液回流减少水肿中起到了重要的作用。这可能会在肿瘤新生血管预防、糖尿病视网膜病变、血管渗透性疾病、组织水肿等研究过程中作为研究的焦点。
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