Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia
Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia
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DOI：
10.1172/jci71090
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发表时间：
2014-01-01
影响因子：
15.9
通讯作者：
Wang, Lianchun
中科院分区：
文献类型：
--
作者：
Zhang, Bing;Xiao, Wenyuan;Wang, Lianchun
先天性膈疝（CDH）是一种常见的出生畸形，其病因多种多样。在这项研究中，我们报道了鼠内皮（Ndst1（ECKO）小鼠）中硫酸乙酰肝素生物合成酶NDST1的消融破坏了膈肌的血管发育，从而导致缺氧以及随后的膈肌发育不全和CDH。有趣的是，Ndst1（ECKO）小鼠中表现出的表型与在slit同源物3（Slit3）敲除小鼠中观察到的发育缺陷相似。此外，编码SLIT3同源受体的基因roundabout同源物4（Robo4）引入杂合突变，加剧了膈肌和CDH的血管发育缺陷。 NDST1 缺陷会减少 SLIT3，但不会减少 ROBO4 与内皮硫酸乙酰肝素的结合，并减弱通常由 SLIT3-ROBO4 信号传导引起的 EC 迁移和体内新血管形成。总之，这些数据表明 SLIT3 向 ROBO4 的硫酸乙酰肝素呈递促进了该信号级联的启动。因此，我们的结果表明，NDST1 的缺失会导致膈肌血管发育缺陷和 CDH，并且硫酸乙酰肝素在血管发育过程中促进血管生成 SLIT3-ROBO4 信号传导。
Congenital diaphragmatic hernia (CDH) is a common birth malformation with a heterogeneous etiology. In this study, we report that ablation of the heparan sulfate biosynthetic enzyme NDST1 in murine endothelium (Ndst1(ECKO) mice) disrupted vascular development in the diaphragm, which led to hypoxia as well as subsequent diaphragm hypoplasia and CDH. Intriguingly, the phenotypes displayed in Ndst1(ECKO) mice resembled the developmental defects observed in slit homolog 3 (Slit3) knockout mice. Furthermore, introduction of a heterozygous mutation in roundabout homolog 4 (Robo4), the gene encoding the cognate receptor of SLIT3, aggravated the defect in vascular development in the diaphragm and CDH. NDST1 deficiency diminished SLIT3, but not ROBO4, binding to endothelial heparan sulfate and attenuated EC migration and in vivo neovascularization normally elicited by SLIT3-ROBO4 signaling. Together, these data suggest that heparan sulfate presentation of SLIT3 to ROBO4 facilitates initiation of this signaling cascade. Thus, our results demonstrate that loss of NDST1 causes defective diaphragm vascular development and CDH and that heparan sulfate facilitates angiogenic SLIT3-ROBO4 signaling during vascular development.