Fibulin-5 functions as an endogenous angiogenesis inhibitor
Fibulin-5 functions as an endogenous angiogenesis inhibitor
复制标题
DOI：
10.1038/labinvest.3700594
复制
发表时间：
2007-08-01
影响因子：
5
通讯作者：
Davis, Elaine C.
中科院分区：
文献类型：
--
作者：
Sullivan, Kaitlyn M.;Bissonnette, Rachel;Davis, Elaine C.
去除小鼠的纤毛蛋白-5基因(Fbln5)会导致皮肤松弛、肺气肿和血管扭曲。此外，fbln5(-)/(-)动物的全身和皮肤血管出芽明显增加。根据这些观察，我们假设在缺乏内源性纤维蛋白-5的情况下，血管萌发的调节会减弱。为了验证这一假说，我们对来自长胸动脉的血管芽进行了量化，并将聚乙烯醇海绵植入野生型和fbln5(-)/(-)小鼠的皮下，以评估纤维血管的侵袭。结果显示，与野生型小鼠相比，fbln5(-)/(-)小鼠的血管原位萌发显著增加，血管侵袭显著增加，成纤维细胞迁移到去除的海绵中没有增加。在野生型小鼠身上的定位表明，该蛋白存在于海绵周围已建立的血管中内皮细胞(ECs)的旁边，并作为海绵内新形成的松散结缔组织的组成部分。这些结果表明，纤毛蛋白-5在内皮细胞的初始萌发和/或迁移过程中可能起到抑制分子的作用。为了阐明在没有纤毛蛋白-5的情况下血管生成增加的分子机制，对野生型和fbln5(-)/(-)小鼠海绵植入12d后血管内皮生长因子(VEGF)和血管生成素(Angs)的表达进行了检测。定量RT-PCR显示，与野生型小鼠相比，fbln5(-)/(-)小鼠海绵侵袭区的VEGF和所有三种Ang的信息水平都增加了几倍。与野生型细胞相比，体外分离的fbln5(-)/(-)小鼠主动脉平滑肌细胞中Ang-1的表达也增加(30倍)，而Ang-1介导的转录因子ESE-1的表达没有变化。综上所述，这些结果表明，在没有纤维蛋白-5的情况下，正常的血管生成过程被增强。
Ablation of the fibulin-5 gene (fbln5) in mice results in loose skin, emphysematous lungs and tortuous vessels. Additionally, fbln5 (-)/(-) animals display an apparent increase in vascular sprouting from systemic and cutaneous vessels. From these observations, we hypothesized that a de-regulation of vascular sprouting occurs in the absence of endogenous fibulin-5. To test this hypothesis, vascular sprouts from the long thoracic artery were quantified and polyvinyl alcohol sponges were implanted subcutaneously in wild-type and fbln5 (-)/(-) mice to assess fibrovascular invasion. Results showed a significant increase in in situ sprouting from vessels in fbln5 (-)/(-) mice and a significant increase in vascular invasion, with no increase in fibroblast migration, into sponges removed from fbln5 (-)/(-) mice compared with wild-type mice. Localization of fibulin-5 in wild-type mice showed the protein to be present subjacent to endothelial cells (ECs) in established vessels at the periphery of the sponge, and as a component of the newly formed, loose connective tissue within the sponge. These results suggest that fibulin-5 could function as an inhibitor molecule in initial sprouting and/or migration of ECs. To elucidate the molecular mechanism that drives the increased angiogenesis in the absence of fibulin-5, expression of vascular endothelial growth factor (VEGF) and the angiopoietins (Angs) was determined in sponges implanted for 12 days in wild- type and fbln5 (-)/(-) mice. Quantitative RT-PCR showed message levels for VEGF and all three Angs to be elevated by several fold in the area of invasion of sponges from fbln5 (-)/(-) mice compared with wild-type mice. Expression of Ang-1 was also shown to be elevated (30- fold) in vitro in aortic smooth muscle cells isolated from fbln5 (-)/(-) mice when compared with wild-type cells, with no change in the expression of the Ang-1 mediating transcription factor, ESE-1. Taken together, these results suggest that the normal angiogenic process is enhanced in the absence of fibulin-5.