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

1.采用棉线诱导小鼠增生性炎症模型，研究了肉芽组织血管生成的调控作用。棉线皮下植入小鼠背部3 ~ 7天肉芽组织中血红蛋白含量逐渐升高。肉芽组织中血管内皮生长因子（VEGF）和血管生成素-1的水平也在同一时间点升高。7 ~ 28 d肉芽组织中血红蛋白含量和VEGF水平下降。肉芽组织内皮抑素和血管生成素-2水平在第14天升高。这些结果表明，VEGF和血管生成素-1参与血管生成，血管生成素-2和内皮抑素诱导血管生成终止。在组氨酸脱羧酶缺陷小鼠中，棉线诱导的肉芽组织中血管生成和新血管成熟出现缺陷。hdl -缺陷小鼠肉芽组织中VEGF和血管生成素-1水平明显低于野生型小鼠。注射抗VEGF抑制组胺诱导的血管生成素-1生成，注射VEGF增加血管生成素-1水平，降低血管生成素-2和内皮抑素水平。这些结果表明，组胺诱导VEGF的产生，VEGF上调血管生成素-1，下调血管生成素-2和内皮抑素的产生。我们利用小鼠巨噬细胞样细胞系RAW264建立筛选系统，寻找诱导VEGF生成的化合物，发现磷酸二酯酶IV抑制剂在巨噬细胞中强烈诱导VEGF生成。诱导内源性VEGF生成的化合物将有助于加速伤口愈合。

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.