Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation
Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation
复制标题
DOI：
10.1038/labinvest.2009.37
复制
发表时间：
2009-07-01
影响因子：
5
通讯作者：
Kato, Mitsuyasu
中科院分区：
文献类型：
--
作者：
Itoh, Fumiko;Itoh, Susumu;Kato, Mitsuyasu
转化生长因子-β通过两种I型受体调节血管发育：激活素受体样激酶(ALK)1和ALK5，每一种受体激活不同的下游Smad通路。内皮细胞(EC)特异性的ALK1促进EC的增殖和迁移，而普遍表达的ALK5抑制这两个过程。由于ALK1需要Alk5的激酶活性才能最佳激活，因此内皮细胞中缺乏Alk5导致两个Smad通路在转化生长因子-β刺激下的缺陷磷酸化。为了了解为什么通过ALK1和Alk5传递的转化生长因子-β信号对内皮细胞有相反的影响，以及这种作用是否发生在体内，我们仔细比较了Alk5敲除(Alk5(Ki/Ki))小鼠的表型，其中Alk5 L45环中的天冬氨酸残基266被丙氨酸残基取代，与Alk5敲除(Alk5(-/-))小鼠的表型进行了比较。Alk5(KI/KI)小鼠在E10.5-11.5出现血管生成缺陷，胚胎致死。尽管Alk5(Ki/Ki)小鼠的表型与Alk5(-/-)小鼠非常相似，但在Alk5(Ki/Ki)小鼠胚胎中形成的血管的层次结构比Alk5(-/-)突变小鼠更发达。因此，Alk5中的L45环突变部分挽救了Alk5(-/-)胚胎中最早的血管缺陷。这项研究支持了我们先前的观察，即体内血管成熟需要转化生长因子-β/ALK1/骨形态发生蛋白-Smad和转化生长因子-β/碱性磷酸酶/激活素-Smad两条通路来维持正常的血管发育。实验室调查(2009年)89800-810；doi：10.1038/Labinvest.2009.37；在线发布
Transforming growth factor (TGF)-beta regulates vascular development through two type I receptors: activin receptor-like kinase (ALK) 1 and ALK5, each of which activates a different downstream Smad pathway. The endothelial cell (EC)-specific ALK1 increases EC proliferation and migration, whereas the ubiquitously expressed ALK5 inhibits both of these processes. As ALK1 requires the kinase activity of ALK5 for optimal activation, the lack of ALK5 in ECs results in defective phosphorylation of both Smad pathways on TGF-beta stimulation. To understand why TGF-beta signaling through ALK1 and ALK5 has opposing effects on ECs and whether this takes place in vivo, we carefully compared the phenotype of ALK5 knock-in (ALK5(KI/KI)) mice, in which the aspartic acid residue 266 in the L45 loop of ALK5 was replaced by an alanine residue, with the phenotypes of ALK5 knock-out (ALK5(-/-)) and wild-type mice. The ALK5(KI/KI) mice showed angiogenic defects with embryonic lethality at E10.5-11.5. Although the phenotype of the ALK5(KI/KI) mice was quite similar to that of the ALK5(-/-) mice, the hierarchical structure of blood vessels formed in the ALK5(KI/KI) embryos was more developed than that in the ALK5(-/-) mutants. Thus, the L45 loop mutation in ALK5 partially rescued the earliest vascular defects in the ALK5(-/-) embryos. This study supports our earlier observation that vascular maturation in vivo requires both TGF-beta/ALK1/BMP-Smad and TGF-beta/ALK5/activin-Smad pathways for normal vascular development. Laboratory Investigation (2009) 89, 800-810; doi:10.1038/labinvest.2009.37; published online 27 April 2009