长期低氧对胎盘血管生成的影响及分子机制

胎盘血管的生成和血流量的调节直接决定着胎儿的生长及存活。研究发现相对于子宫，胎盘的血管生长是处在长期低氧的条件（2%～8% O2）下完成的。而目前众多研究中关于低氧对胎盘血管生成的影响所采用的细胞模型大多是建立在常规氧分压(21% O2)条件下的原代内皮细胞，且仅限于短期（4-120小时）的低氧处理研究。本课题将突破常规的低氧研究模式，首创性地建立真正意义的延续体内低氧条件的胎盘血管内皮细胞模型，即将分离出的内皮细胞直接放入低氧条件下进行长期（3% O2, 20-25天）培养，并分别从组织，细胞以及分子水平深入探讨长期低氧对胎盘血管生成的影响，阐明参与其调节的信号传导通路和信号分子，重新认识低氧诱导因子在此长期低氧研究模式中的作用。本课题的完成将为生理性低氧微环境下调控血管生成及血流量提供新的研究靶点，同时也为研究低氧在疾病中的作用，包括肿瘤生成，创面愈合等, 提供新的实验模式和研究思路。

Angiogenesis and vasodilatation are two critical processes controlling the dramatic increases in placental blood flow,which is directly correlated with fetal growth and survival. It is well demonstrated that the development of human placental vasculature took place under hypoxia throughout the pregnancy conditions in comparison with uterus. However, the vast majority of our knowledge on the cellular and molecular mechanisms controlling endothelial function has been built on the endothelial cell models derived under the standard cell culture normoxia (21% O2). In this study, we have successfully established in vitro HUVE cell models under chronic hypoxia (3% O2), which falls within the physiological range of O2 (2-8%) in human placentas at term. And the effects of chronic hypoxia on placental angiogenesis were investigated at tissue, cellular and molecular levels, respectively. Also, the functional roles of HIFs (hypoxia-inducible factors) in the placental angiogenesis under this chronic hypoxic conditions were re-evaluated. Thus, a better understanding of chronic physiological hypoxia regulation of endothelial function may in the future assist us to manipulate tissue blood flow, ultimately controlling tissue growth under physiological and pathological conditions, including of tumor development and wound healing.