Induction and termination of angiogenesis by regulation of angiogenesis-related factor production

1.用棉线诱导的小鼠增生性炎症模型检测肉芽组织中血管生成的调节。在小鼠背部皮下植入棉线后，肉芽组织中的血红蛋白含量从3天到7天逐渐增加。肉芽组织中血管内皮生长因子（VEGF）和血管生成素-1的水平也在相同的时间点增加。第7 ~ 28天，肉芽组织中血红蛋白含量和VEGF水平下降。肉芽组织中内皮抑素和血管生成素-2的水平在14天时增加。提示VEGF和Angiopoietin-1参与了新生血管的形成，Angiopoietin-2和Endostatin诱导了新生血管的终止。2.组氨酸脱羧酶缺陷小鼠模型中，棉线诱导的肉芽组织中新生血管的形成和成熟均受到抑制。血管内皮生长因子和血管生成素-1的水平显着低于野生型小鼠在HDLC缺陷型小鼠的肉芽组织。注射抗VEGF抑制组胺诱导的血管生成素-1的产生，注射VEGF增加血管生成素-1的水平，但降低血管生成素-2和内皮抑素的水平。这些结果表明，组胺可诱导VEGF的产生，而VEGF可上调Ang-1的表达，下调Ang-2和Endostatin的表达。3.我们建立了小鼠巨噬细胞样细胞株RAW 264筛选体系，以寻找诱导VEGF产生的化合物，发现磷酸二酯酶IV抑制剂可强烈诱导巨噬细胞产生VEGF。诱导内源性VEGF产生的化合物可用于加速伤口愈合。

1.Regulation of angiogenesis in granulation tissues was examined using cotton thread-induced proliferative inflammation model in mice. Subcutaneous implantation of a cotton thread in the dorsum of mice induced gradual increase in the hemoglobin content in the granulation tissues from 3 to 7 days. The levels of vascular endothelial growth factor (VEGF) and angiopoietin-1 in the granulation tissues were also increased over the same time points. Then, the hemoglobin content and the level of VEGF in the granulation tissues were decreased from 7 to 28 days. The levels of endostatin and angiopoietin-2 in the granulation tissues were increased at 14 days. These results suggest that VEGF and angiopoietin-1 are involved in the angiogenesis, and angiopoietin-2 and endostatin induce the termination of angiogenesis.2.In histidine decarboxylase-deficient mice, angiogenesis and maturation of new vessels in the cotton thread-induced granulation tissues were defected. The levels of VEGF and angiopoietin-1 in the granulation tissues in HDC-deficient mice were significantly lower than those in wild-type mice. The injection of anti-VEGF inhibited histamine-induced angiopoietin-1 production, and the injection of VEGF increased angiopoietin-1 level but decreased the levels of angiopoietin-2 and endostatin. These results suggest that histamine induces VEGF production and VEGF up-regulates angiopoietin-1 but down-regulates angiopoietin-2 and endostatin production.3.We established the screening system using murine macrophage-like cell line RAW264 to find the compound that induces VEGF production, and found that phosphodiesterase IV inhibitors strongly induced VEGF production in macrophages. The compound that induces endogenous VEGF production would be useful for acceleration of wound healing.