Antagonism and synergy between extracellular BMP modulators Tsg and BMPER balance blood vessel formation
Antagonism and synergy between extracellular BMP modulators Tsg and BMPER balance blood vessel formation
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DOI：
10.1242/jcs.122333
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发表时间：
2013-07-15
影响因子：
4
通讯作者：
Moser, Martin
中科院分区：
文献类型：
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作者：
Heinke, Jennifer;Juschkat, Maria;Moser, Martin
血管的生长和再生是胚胎发育和成人疾病的关键过程。骨形态发生蛋白（BMP）家族成员是已知在血管发育中起关键作用的生长因子。BMP途径由细胞外BMP调节剂如BMP内皮细胞前体衍生调节剂（BMPER）控制，我们先前报道其以浓度依赖性方式对内皮细胞起促血管生成作用。在这里，我们探讨了其他BMP调节剂，特别是Tsg，对内皮细胞行为的功能，并将其与BMPER进行比较。在Matrigel试验中，BMP调节剂chordin和noggin没有刺激作用;然而，gremlin和Tsg增强人脐静脉内皮细胞（HUVEC）发芽。由于Tsg的激活动力学与BMPER的激活动力学相似，我们进一步研究了Tsg对内皮细胞的促血管生成作用。Tsg在小鼠Matrigel plug试验中促进内皮细胞向内生长，以及在体外促进HUVEC发芽、迁移和增殖，这依赖于Akt、Erk和Smad信号通路以浓度依赖性方式激活。令人惊讶的是，Tsg的沉默也增加了HUVEC发芽、迁移和增殖，这再次与Akt、Erk和Smad信号通路激活相关。此外，我们发现Tsg和BMPER相互干扰，以增强促血管生成事件。然而，在体内的Tsg以及BMPER的存在下，是必要的定期发展的斑马鱼血管。两者合计，我们的研究结果表明，BMPER和Tsg保持微调平衡，控制BMP通路的活动，是必要的血管细胞的稳态。
Growth and regeneration of blood vessels are crucial processes during embryonic development and in adult disease. Members of the bone morphogenetic protein (BMP) family are growth factors known to play a key role in vascular development. The BMP pathway is controlled by extracellular BMP modulators such as BMP endothelial cell precursor derived regulator (BMPER), which we reported previously acts proangiogenically on endothelial cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators, especially Tsg, on endothelial cell behaviour and compare them to BMPER. In Matrigel assays, BMP modulators chordin and noggin had no stimulatory effect; however, gremlin and Tsg enhanced human umbilical vein endothelial cell (HUVEC) sprouting. As the activation dynamics of Tsg were similar to those of BMPER, we further investigated the proangiogenic effect of Tsg on endothelial cells. Tsg enhanced endothelial cell ingrowth in the mouse Matrigel plug assay as well as HUVEC sprouting, migration and proliferation in vitro, dependent on Akt, Erk and Smad signalling pathway activation in a concentration-dependent manner. Surprisingly, silencing of Tsg also increased HUVEC sprouting, migration and proliferation, which is again associated with Akt, Erk and Smad signalling pathway activation. Furthermore, we reveal that Tsg and BMPER interfere with each other to enhance proangiogenic events. However, in vivo the presence of Tsg as well as of BMPER is mandatory for regular development of the zebrafish vasculature. Taken together, our results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular cell homeostasis.