Endothelial follistatin-like-1 regulates the postnatal development of the pulmonary vasculature by modulating BMP/Smad signaling.
Endothelial follistatin-like-1 regulates the postnatal development of the pulmonary vasculature by modulating BMP/Smad signaling.
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DOI：
10.1177/2045893217702340
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发表时间：
2017-03
影响因子：
2.6
通讯作者：
Gosens R
中科院分区：
文献类型：
--
作者：
Tania NP;Maarsingh H;T Bos IS;Mattiotti A;Prakash S;Timens W;Gunst QD;Jimenez-Borreguero LJ;Schmidt M;van den Hoff MJB;Gosens R
骨形态发生蛋白(BMP)信号调节血管平滑肌成熟、内皮细胞增殖和管状形成。内源性BMP拮抗剂Follistatin-like 1(FSTL1)在发育中的小鼠肺血管内皮细胞中高表达，提示其在肺血管形成和血管动态平衡中发挥作用。本研究旨在探讨FSTL1在肺血管内皮细胞中的作用。为此，使用Tie2-cre驱动的FSTL1-KO小鼠(FSTL1-Eko小鼠)，有条件地从内皮细胞和内皮来源的细胞中删除FSTL1。内皮特异的FSTL1缺失在出生后是致命的，因为∼70%的FSTL1-EKO小鼠在出生后三周死亡。与对照组相比，FSTL1从内皮细胞中缺失导致出生后三周的右室输出量减少。这与肺血管重塑有关，因为与对照组相比，FSTL1-EKO小鼠在三周时肌动蛋白阳性的小肺血管的百分比增加。与对照组相比，FSTL1内皮细胞缺失导致Smad1/5/8信号通路激活，BMP/Smad调节的Jagged1、Endoglin和Gata2基因在出生后1周表达增加。此外，在出生后1周，由Gata2驱动的强大的血管收缩因子Endothelin-1的表达在mRNA和蛋白水平上都比对照组增加。在3周时，FSTL1-EKO小鼠的Jagged1减少，而Endoglin和Endothelin-1没有变化。总之，肺内皮细胞FSTL1的缺失与BMP调节基因升高、小肺血管重塑受损和右室输出量减少有关。
Bone morphogenetic protein (BMP) signaling regulates vascular smooth muscle maturation, endothelial cell proliferation, and tube formation. The endogenous BMP antagonist Follistatin-like 1 (Fstl1) is highly expressed in pulmonary vascular endothelium of the developing mouse lung, suggesting a role in pulmonary vascular formation and vascular homeostasis. The aim of this study was to investigate the role of Fstl1 in the pulmonary vascular endothelium. To this aim, Fstl1 was conditionally deleted from endothelial and endothelial-derived cells using Tie2-cre driven Fstl1-KO mice (Fstl1-eKO mice). Endothelial-specific Fstl1 deletion was postnatally lethal, as ∼70% of Fstl1-eKO mice died at three weeks after birth. Deletion of Fstl1 from endothelium resulted in a reduction of right ventricular output at three weeks after birth compared with controls. This was associated with pulmonary vascular remodeling, as the percentage of actin-positive small pulmonary vessels was increased at three weeks in Fstl1-eKO mice compared with controls. Endothelial deletion of Fstl1 resulted in activation of Smad1/5/8 signaling and increased BMP/Smad-regulated gene expression of Jagged1, Endoglin, and Gata2 at one week after birth compared with controls. In addition, potent vasoconstrictor Endothelin-1, the expression of which is driven by Gata2, was increased in expression, both on the mRNA and protein levels, at one week after birth compared with controls. At three weeks, Jagged1 was reduced in the Fstl1-eKO mice whereas Endoglin and Endothelin-1 were unchanged. In conclusion, loss of endothelial Fstl1 in the lung is associated with elevated BMP-regulated genes, impaired small pulmonary vascular remodeling, and decreased right ventricular output.