Angiogenic factors stimulate tubular branching morphogenesis of sonic hedgehog-deficient lungs
Angiogenic factors stimulate tubular branching morphogenesis of sonic hedgehog-deficient lungs
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DOI：
10.1016/j.ydbio.2006.11.029
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发表时间：
2007-03-15
影响因子：
2.7
通讯作者：
Post, Martin
中科院分区：
文献类型：
--
作者：
van Tuyl, Minke;Groenman, Freek;Post, Martin
Sonic Hedgehog(Shh)缺陷小鼠有严重的肺分支缺陷。最近的研究表明，Hedgehog信号参与了血管的发育，Shh缺陷小鼠的气道分支减少可能是由于肺血管的异常形成。因此，我们通过Shh/Tie21acZ复合小鼠内皮细胞特异性LacZ表达和Pecam-1免疫组织化学研究Shh在肺血管发育中的作用。E11.5-13.5Shh缺陷小鼠肺血管床减少，但与气道分支减少相适应。然而，当E12.5Shh缺陷肺培养4-6天时，与野生型肺相比，血管网络恶化。E12.5-13.5Shh缺陷型与野生型肺组织中血管内皮生长因子(VEGF)及其受体VEGFR2(KDR/FTK-1)的表达无明显差异。相反，血管生成素-1(Ang1)，而不是Ang2或血管生成素受体Tie2，在Shh缺失突变的E12.5-E13.5肺中表达下调。单独重组Ang1不能恢复Shh缺陷性肺的体外分枝形态发生。相反，血管生成因子成纤维细胞生长因子-2单独或与Ang1联合使用，在体外可促进Shh缺陷肺的血管形成和管状生长及分支。血管生成因子不能克服Shh缺失区肺内平滑肌细胞分化减少的现象。这些结果表明，Shh基因缺陷小鼠早期血管发育由VEGF/VEGFR2信号转导正常进行，而后期血管发育和Ang/Tie2信号转导通路介导的原始网络的稳定存在缺陷，导致血管网络异常。血管生成因子如FGF2和Ang1刺激血管形成部分恢复Shh缺陷肺的管状生长和分支，提示血管形成是分支形态发生所必需的。(C)2006 Elsevier Inc.保留所有权利。
Sonic Hedgehog (Shh)-deficient mice have a severe lung branching defect. Recent studies have shown that hedgehog signaling is involved in vascular development and it is possible that the diminished airway branching in Shh-deficient mice is due to abnormal pulmonary vasculature formation. Therefore, we investigated the role of Shh in pulmonary vascular development using Shh/Tie21acZ compound mice, which exhibit endothelial cell-specific LacZ expression, and Pecam-1 immunohistochemistry. In E 11.5-13.5 Shh-deficient mice, the pulmonary vascular bed is decreased, but appropriate to the decrease in airway branching. However, when E 12.5 Shh-deficient lungs were cultured for 4-6 days, the vascular network deteriorated compared to wild-type lungs. The expression of vascular endothelial growth factor (Vegf) or its receptor Vegfr2 (KDR/Ftk-1) was not different between E12.5-13.5 Shh-deficient and wild-type lungs. In contrast, angiopoietin-1 (Ang1), but not Ang2 or the angiopoietin receptor Tie2, mRNA expression was downregulated in E12.5-E13.5 lungs of Shh null mutants. Recombinant Ang1 alone was unable to restore in vitro branching morphogenesis in Shh-deficient lungs. Conversely, the angiogenic factor fibroblast growth factor (Fgf)-2 alone or in combination with Ang1, increased vascularization and tubular growth and branching of Shh-deficient lungs in vitro. The angiogenic factors did not overcome the reduced smooth muscle cell differentiation in the Shh null lungs. These data indicate that early vascular development, mediated by Vegf/Vegfr2 signaling proceeds normally in Shh-deficient mice, while later vascular development and stabilization of the primitive network mediated by the Ang/Tie2 signaling pathway are defective, resulting in an abnormal vascular network. Stimulation of vascularization with angiogenic factors such as Fgf2 and Ang1 partially restored tubular growth and branching in Shh-deficient lungs, suggesting that vascularization is required for branching morphogenesis. (c) 2006 Elsevier Inc. All rights reserved.