Regano Donatella, Visintin Alessia, Clapero Fabiana, Bussolino Federico, Valdembri Donatella, Maione Federica, Serini Guido, Giraudo Enrico
From the Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Torino, Italy (D.R., A.V., F.C., F.B., D.V., F.M., G.S., E.G.); Department of Science and Drug Technology, University of Torino, Italy (D.R., A.V., F.M., E.G.); and Department of Oncology, University of Torino School of Medicine, Candiolo, Italy (F.C., F.B., D.V., G.S.).
Arterioscler Thromb Vasc Biol. 2017 Sep;37(9):1710-1721. doi: 10.1161/ATVBAHA.117.308226. Epub 2017 Jul 20.
Molecular pathways governing blood vessel patterning are vital to vertebrate development. Because of their ability to counteract proangiogenic factors, antiangiogenic secreted Sema3 (class 3 semaphorins) control embryonic vascular morphogenesis. However, if and how Sema3 may play a role in the control of extraembryonic vascular development is presently unknown.
By characterizing genetically modified mice, here, we show that surprisingly Sema3F acts instead as a selective extraembryonic, but not intraembryonic proangiogenic cue. Both in vivo and in vitro, in visceral yolk sac epithelial cells, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, a transcription factor that drives the expression of proangiogenic genes, such as the microRNA cluster 17/92. In -null yolk sacs, the transcription of Myc-regulated microRNA 17/92 cluster members is impaired, and the synthesis of Myc and microRNA 17/92 foremost antiangiogenic target Thbs1 (thrombospondin 1) is increased, whereas Vegf (vascular endothelial growth factor) signaling is inhibited in yolk sac endothelial cells. Consistently, exogenous recombinant Sema3F inhibits the phosphorylation-dependent degradation of Myc and the synthesis of Thbs1 in mouse F9 teratocarcinoma stem cells that were in vitro differentiated in visceral yolk sac epithelial cells. mice placentas are also highly anemic and abnormally vascularized.
Sema3F functions as an unconventional Sema3 that promotes extraembryonic angiogenesis by inhibiting the Myc-regulated synthesis of Thbs1 in visceral yolk sac epithelial cells.
调控血管模式的分子途径对脊椎动物发育至关重要。抗血管生成分泌型Sema3（3类信号素）能够对抗促血管生成因子，从而控制胚胎血管形态发生。然而，Sema3是否以及如何在胚胎外血管发育的调控中发挥作用目前尚不清楚。
通过对基因修饰小鼠的特征分析，我们发现令人惊讶的是，Sema3F反而作为一种选择性的胚胎外而非胚胎内促血管生成信号。在体内和体外，在内脏卵黄囊上皮细胞中，Sema3F发出信号抑制Myc的磷酸化依赖性降解，Myc是一种驱动促血管生成基因（如微小RNA簇17/92）表达的转录因子。在Sema3F基因敲除的卵黄囊中，Myc调控的微小RNA 17/92簇成员的转录受损，Myc和微小RNA 17/92最重要的抗血管生成靶点Thbs1（血小板反应蛋白1）的合成增加，而卵黄囊内皮细胞中的Vegf（血管内皮生长因子）信号传导受到抑制。同样，外源性重组Sema3F抑制在体外分化为内脏卵黄囊上皮细胞的小鼠F9畸胎瘤干细胞中Myc的磷酸化依赖性降解和Thbs1的合成。Sema3F基因敲除小鼠的胎盘也严重贫血且血管化异常。
Sema3F作为一种非常规的Sema3，通过抑制内脏卵黄囊上皮细胞中Myc调控的Thbs1合成来促进胚胎外血管生成。
