CSE/H2S和CBS/H2S差异性感受缺氧与差异性调控VEGFR2信号通路在缺氧诱导血管新生中的作用及机制研究

Hydrogen sulfide(H2S) is an endogenous gas molecule with important physiological relevance. It has been found to have proangiogenic effect with VEGFR2 as its target molecule. Angiogenesis is usually an adaptive process to tissue hypoxia. We have found in our previous study that downregulating CSE (one of H2S-producing enzyme) by RNA interference can significantly inhibit the increase of endothelial cells migration induced by hypoxia, while downregulating CBS (another H2S-producing enzyme) has no such effect,indicating CSE/H2S and CBS/H2S are playing different roles in hypoxia-induced angiogenesis. The significance of co-existence of two H2S-producing systems (CSE/H2S and CBS/ H2S) in vascular endothelial cells is still unclear. We thought that there might be two reasons: 1、Different extracellular stimuli could exert different effect on CSE and CBS, resulting in differentially sensing the stimuli by cells. 2、In our previous study, we found that CSE and CBS are distributed differently in a cell, suggesting the H2S produced by CSE or CBS has different effective concentration ranges. Thus, CSE and CBS may have different target proteins, resulting in specific response of endothelial cells to different stimuli. In this project, we will further testify the different roles of the two systems in hypoxia-induced angiogenesis, and study the effect and mechanism of the differential regulation of CSE and CBS by hypoxia under the model of hypoxia-induced angiogenesis. In addition, whether CSE/H2S and CBS/H2S regulated VEGFR2 signalling pathways differently would be further tested. This study will suggest the importance role of co-existence of CSE/ H2S and CBS/ H2S in differentially sensing and specifically responding to extracellular stimuli.

硫化氢（H2S）是具有重要生理活性的内源性气体分子，可直接激活VEGFR2促进血管新生。血管新生是机体对缺氧的适应性反应。我们发现，H2S生成酶CSE/H2S系统参与了缺氧促内皮细胞迁移的过程，而另一个系统CBS/H2S则在该过程中无作用。提示两种生成系统在缺氧诱导血管新生中的作用不同。我们猜测两种系统并存于内皮细胞的原因有：1、不同的胞外刺激将对CSE、CBS产生不同的作用，实现细胞对不同刺激的差异性感受。2、前期研究发现CSE和CBS在内皮细胞中分布不同，提示它们所产生H2S的有效浓度范围不同，则其靶分子很可能不同。本项目中，我们将进一步确认两种系统在缺氧诱导血管新生中作用的差异，深入研究缺氧对CSE、CBS的差异性调节，并研究两个系统产生的H2S是否均以VEGFR2为靶分子。该研究将初步揭示CSE/ H2S和CBS/ H2S系统在细胞区别感受胞外刺激并产生特异性应答反应中的意义。