SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling
SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling
复制标题
DOI：
10.1161/circresaha.116.308483
复制
发表时间：
2016-09-16
影响因子：
20.1
通讯作者：
Kim, Injune
中科院分区：
文献类型：
--
作者：
Kim, Kangsan;Kim, Il-Kug;Kim, Injune
理由：血管内皮生长因子 (VEGF) 信号传导是血管生成的关键途径，需要高度协调的调节。尽管Notch通路通过负反馈介导的过度VEGF活性抑制是众所周知的，但增强VEGF信号传导的正反馈控制仍然知之甚少。转录因子 Sox17 对于血管生成是不可或缺的，但其与 VEGF 信号传导的关系尚不清楚。其他红袜队成员对血管生成的贡献也有待确定。目的：揭示Sox的另一个成员Sox7与Sox17在发育性血管生成中的遗传相互作用及其与VEGF信号传导的功能关系。方法和结果：Sox7在内皮细胞中特异性表达，其整体和内皮特异性缺失导致小鼠胚胎致死，血管生成严重受损，与Sox17在表达和功能上基本重叠。有趣的是，Sox7 和 Sox17 的复合杂合性表型复制了 Sox7 或 Sox17 纯合敲除的血管缺陷，表明 Sox7 和 Sox17 的遗传合作对其组合基因剂量敏感。 VEGF 信号通过 mTOR 通路上调血管生成中 Sox7 和 Sox17 的表达。此外，Sox7 和 Sox17 促进血管生成血管中 VEGFR2（VEGF 受体 2）的表达，表明 VEGF 信号传导和 SoxF 之间存在正反馈循环。结论：我们的研究结果表明，SoxF 转录因子通过充当 VEGF 信号传导的正反馈调节剂，在发育性血管生成中是不可或缺的参与者。
Rationale: Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined. Objective: To reveal the genetic interaction of Sox7, another Sox member, with Sox17 in developmental angiogenesis and their functional relationship with VEGF signaling.Methods and Results: Sox7 is expressed specifically in endothelial cells and its global and endothelial-specific deletion resulted in embryonic lethality with severely impaired angiogenesis in mice, substantially overlapping with Sox17 in both expression and function. Interestingly, compound heterozygosity for Sox7 and Sox17 phenocopied vascular defects of Sox7 or Sox17 homozygous knockout, indicating that the genetic cooperation of Sox7 and Sox17 is sensitive to their combined gene dosage. VEGF signaling upregulated both Sox7 and Sox17 expression in angiogenesis via mTOR pathway. Furthermore, Sox7 and Sox17 promoted VEGFR2 (VEGF receptor 2) expression in angiogenic vessels, suggesting a positive feedback loop between VEGF signaling and SoxF.Conclusions: Our findings demonstrate that SoxF transcription factors are indispensable players in developmental angiogenesis by acting as positive feedback regulators of VEGF signaling.