Tetraspanin18 regulates angiogenesis through VEGFR2 and Notch pathways.
Tetraspanin18 regulates angiogenesis through VEGFR2 and Notch pathways.
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DOI：
10.1242/bio.050096
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发表时间：
2021-02-25
期刊：
影响因子：
2.4
通讯作者：
Gill PS
中科院分区：
文献类型：
--
作者：
Li GX;Zhang S;Liu R;Singh B;Singh S;Quinn DI;Crump G;Gill PS
VEGF途径是血管发生（形成初级血管网络）的关键。它也是血管生成所必需的，导致血管的发芽和修剪以产生成熟的树枝状结构。Notch通路对于动脉-静脉特化和新生血管的成熟至关重要。我们已经确定，Tspan 18，四跨膜蛋白家族的一员，在斑马鱼和小鼠伤口愈合的发育中的血管中表达，但在成熟的脉管系统中不表达。此外，Tspan 18水平的降低导致异常的血管模式，血管稳定性受损和缺陷的动静脉规格。Tspan 18缺陷降低VEGF、VEGFR 2、Notch 3和EphrinB 2的表达，增加EphB 4、VEGFR 3、Semaphorin 3、Neuropilin和PlexinD 1的表达。此外，Tspan 18缺陷的血管缺陷可以通过VEGFR 2和Notch的异位表达来挽救，但不能通过敲低Semaphorin或丛状蛋白来挽救。功能研究表明，敲低Tspan 18导致内皮细胞迁移，侵袭和管形成减少。Tspan 18在胚胎中具有动态表达，调节血管的发育和成熟，并在创伤愈合过程中重新表达。总结：Tspan 18是一种在内皮细胞中高度限制表达的跨膜蛋白，是VEGF和Notch通路的关键调节因子。它调节动脉-静脉规格、血管模式和血管稳定性。
The VEGF pathway is critically required for vasculogenesis, the formation of the primary vascular network. It is also required for angiogenesis resulting in sprouting and pruning of vessels to generate mature arborizing structures. The Notch pathway is essential for arterial–venous specification and the maturation of nascent vessels. We have determined that Tspan18, a member of the Tetraspanin family, is expressed in developing vessels but not in mature vasculature in zebrafish and mouse wound healing. Moreover, reduction at Tspan18 level resulted in aberrant vascular patterning, impaired vessel stability and defective arterial–venous specification. Tspan18 deficiency reduced VEGF, VEGFR2, Notch3 and EphrinB2, and increased EphB4, VEGFR3, Semaphorin3, Neuropilin and PlexinD1 expression. Furthermore, vascular defects of Tspan18 deficiency could be rescued by ectopic expression of VEGFR2 and Notch, but not by knockdown of Semaphorin or Plexin. Functional studies showed that knockdown of Tspan18 led to reduced endothelial cell migration, invasion and tube formation. Tspan18 has dynamic expression, regulates vascular development and maturation in the embryo with re-expression in adult life in wound healing. Summary: Tspan18 is a transmembrane protein with highly restricted expression in endothelial cells and a critical regulator of VEGF and Notch pathways. It regulates artery–vein specification, vessel patterning and vessel stability.