BACKGROUND Angiogenesis is integral for embryogenesis, and targeting angiogenesis improves the outcome of many pathological conditions in patients. TBX20 is a crucial transcription factor for embryonic development, and its deficiency is associated with congenital heart disease. However, the role of TBX20 in angiogenesis has not been described. METHODS Loss- and gain-of-function approaches were used to explore the role of TBX20 in angiogenesis both in vitro and in vivo. Angiogenesis gene array was used to identify key downstream targets of TBX20. RESULTS Unbiased gene array survey showed that TBX20 knockdown profoundly reduced angiogenesis-associated PROK2 (prokineticin 2) gene expression. Indeed, loss of TBX20 hindered endothelial cell migration and in vitro angiogenesis. In a murine angiogenesis model using subcutaneously implanted Matrigel plugs, we observed that TBX20 deficiency markedly reduced PROK2 expression and restricted intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or its cognate receptor prokr1a also limited angiogenesis. In contrast, overexpression of prok2 or prokr1a rescued the impaired angiogenesis in tbx20-deficient animals. CONCLUSIONS Our study identifies TBX20 as a novel transcription factor regulating angiogenesis through the PROK2-PROKR1 (prokineticin receptor 1) pathway in both development and disease and reveals a novel mode of angiogenic regulation whereby the TBX20-PROK2-PROKR1 signaling cascade may act as a "biological capacitor" to relay and sustain the proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.

中文翻译：

---

TBX20通过Prokineticin 2 Prokineticin受体1途径调节血管生成。

背景技术血管生成对于胚胎发生是必不可少的，并且靶向血管生成改善了患者中许多病理状况的结果。TBX20是胚胎发育的关键转录因子，其缺乏与先天性心脏病有关。然而，尚未描述TBX20在血管生成中的作用。方法采用功能丧失和获得功能的方法来探索TBX20在体内外的血管生成中的作用。血管生成基因阵列用于鉴定TBX20的关键下游靶标。结果无偏基因阵列调查显示，TBX20敲低极大地降低了与血管生成相关的PROK2（促动蛋白2）基因的表达。确实，TBX20的丢失阻碍了内皮细胞的迁移和体外血管生成。在使用皮下植入的Matrigel塞的鼠血管生成模型中，我们观察到TBX20缺乏显着降低了PROK2表达并限制了塞内血管生成。此外，重组PROK2给药增强了鼠后肢缺血中的血管生成和血流恢复。在斑马鱼中，吗啉代反义寡核苷酸对tbx20的瞬时敲低或CRISPR / Cas9对tbx20的遗传破坏损害了血管生成。此外，prok2或其同源受体prokr1a的丢失也限制了血管生成。相反，prok2或prokr1a的过表达挽救了tbx20缺陷动物的血管新生。结论我们的研究确定了TBX20是在发育和疾病中通过PROK2-PROKR1（促动蛋白受体1）途径调节血管生成的新型转录因子，并揭示了一种新型的血管生成调节方式，其中TBX20-PROK2-PROKR1信号级联反应可作为“生物电容器”来中继和维持血管内皮生长因子的促血管生成作用。该途径可能是治疗血管生成失调的疾病的治疗靶标。