色素上皮衍生因子（PEDF）在不同时期婴幼儿血管瘤中的调控作用机制研究

It is widely accepted that dysregulation of angiogenic mediators, such as VEGF, contributes to abnormal formation of capillaries is one of the major molecular mechanisms of infantile hemangioma, which is the most common benign tumor in infantiles, and the severe cases of which are still difficult to treat. However, angiogenic homeostasis is controlled preciously by the balance between angiogenic stimulators and angiogenic inhibitors, and the role of angiogenic inhibitors has been revealed rarely. PEDF has been shown to be a far greater inhibitor of angiogenesis than any other endogenous angiogenic inhibitors and is believed to be the key factor associated with avascularity of the cornea and homeostasis of angiogenesis in retina. In previous studies, we discovered that the expression of PEDF varied significantly in different phases of infantile hemangioma, indicating that PEDF might also play a critical role in the spontaneous regression of infantile hemangioma and might become an important potential therapeutic agent for it. In this studies, we will further explore the mechanisms of PEDF in hemangioma by down-regulation of HIF-1α, MMPs and VEGF expression, inhibition of PI3K/Akt signal pathway, thus further to break the vicious circle of proliferation - hypoxia -upregulation of HIF-1α- proliferation caused by the over-proliferation of endothelial cells and consequently pathological neovascularization and to promote the regression of infantile hemangioma through vivo and vitro experiments. The conclusion of the study may provide a solid theoretical basis for the application of the PEDF in infantile hemangioma treatment.

婴幼儿血管瘤是婴幼儿最常见的良性肿瘤，严重病例治疗棘手。现较多研究关注病灶内促血管生成因子高表达，而从血管生成抑制因子角度探讨血管瘤的发生发展机制却鲜有研究。色素上皮衍生因子(PEDF)就是目前发现的最有效内源性新生血管抑制因子。前期我们研究发现增生期及消退期婴幼儿血管瘤病灶组织内PEDF表达水平存在明显差异，推测PEDF在婴幼儿血管瘤的不同时期可能存在重要调节作用。本研究将进一步通过三维血管瘤血管生成干预、体外血管瘤干细胞培养及干预、裸鼠种植瘤模型干预等手段，研究PEDF能否通过下调HIF-1α、MMPs、VEGF等因子的表达，抑制下游PI3K/Atk信号传导通路，进而打破体内血管瘤病灶快速增殖时，局部相对缺氧环境所造成的增殖-缺氧-HIF-1α上调-促进增殖的恶性循环，促进血管内皮细胞凋亡和病灶消退，成为婴幼儿血管瘤治疗的新希望，使血管瘤治疗有望真正针对其发病机制而展开。

婴幼儿血管瘤是婴幼儿最常见的良性肿瘤，严重病例治疗棘手。现较多研究关注病灶内促血管生成因子高表达，而从血管生成抑制因子角度探讨血管瘤的发生发展机制却鲜有研究。色素上皮衍生因子(PEDF)就是目前发现的最有效内源性新生血管抑制因子。前期我们研究发现增生期及消退期婴幼儿血管瘤病灶组织内PEDF表达水平存在明显差异，推测PEDF在婴幼儿血管瘤的不同时期可能存在重要调节作用。本研究将进一步通过三维血管瘤血管生成干预、体外血管瘤干细胞培养及干预、裸鼠种植瘤模型干预等手段，研究PEDF能否通过下调HIF-1α、MMPs、VEGF等因子的表达，抑制下游PI3K/Atk信号传导通路，进而打破体内血管瘤病灶快速增殖时，局部相对缺氧环境所造成的增殖-缺氧-HIF-1α上调-促进增殖的恶性循环，促进血管内皮细胞凋亡和病灶消退，成为婴幼儿血管瘤治疗的新希望，使血管瘤治疗有望真正针对其发病机制而展开。