Powell J A, Mohamed S N, Kerr J S, Mousa S A
DuPont Pharmaceuticals Company, Wilmington, Delaware 19980, USA.
J Cell Biochem. 2000 Sep 18;80(1):104-14. doi: 10.1002/1097-4644(20010101)80:1<104::aid-jcb90>3.0.co;2-k.
Angiogenesis is a complex process involving endothelial cell migration, proliferation, invasion, and tube formation. Inhibition of these processes might have implications in various angiogenesis-mediated disorders. Because nitric oxide (NO) is known to play a key role in various vascular diseases, the present study was undertaken to determine the role of NO in angiogenesis-mediated processes using the NO donor, S-nitroso N-acetyl penicillamine (SNAP) and S-nitroso N-acetyl glutathione (SNAG). The antiangiogenic efficacy of these NO donors was examined using in vivo and in vitro model systems. The in vitro studies demonstrated the ability of SNAP to inhibit cytokine fibroblast growth factor (FGF2)-stimulated tube formation and serum-induced cell proliferation. The inhibitory effect on cell proliferation by SNAP concentrations above the millimolar range was associated with significant shifts in the concentration of NO metabolites. Furthermore, using the mouse Matrigel implant model and the chick chorioallantoic membrane (CAM) models, SNAP demonstrated maximal inhibitory efficacy (85-95% inhibition) of cytokine (FGF2)-induced neovascularization in both in vivo models. SNAP and SNAG resulted in 85% inhibition of FGF2-induced neovascularization in the mouse Matrigel model when given at 5 mg/kg/day infusion in minipumps during 14 days and 87% inhibition of angiogenesis induced by FGF2 in the CAM when administered a single dose of 50 microg. Thus, NO donors might be a useful tool for the inhibition of angiogenesis associated with human tumor growth, or neovascular, ocular, and inflammatory diseases.
血管生成是一个复杂的过程，涉及内皮细胞迁移、增殖、侵袭和管腔形成。抑制这些过程可能对各种血管生成介导的疾病有影响。由于一氧化氮（NO）在各种血管疾病中起关键作用，因此本研究旨在使用NO供体S-亚硝基-N-乙酰青霉胺（SNAP）和S-亚硝基-N-乙酰谷胱甘肽（SNAG）来确定NO在血管生成介导过程中的作用。使用体内和体外模型系统检测了这些NO供体的抗血管生成功效。体外研究表明，SNAP能够抑制细胞因子成纤维细胞生长因子（FGF2）刺激的管腔形成和血清诱导的细胞增殖。毫摩尔范围以上浓度的SNAP对细胞增殖的抑制作用与NO代谢产物浓度的显著变化有关。此外，使用小鼠基质胶植入模型和鸡胚绒毛尿囊膜（CAM）模型，SNAP在两种体内模型中均显示出对细胞因子（FGF2）诱导的新生血管形成的最大抑制功效（85%-95%抑制）。在小鼠基质胶模型中，当以5mg/kg/天的剂量通过微型泵输注14天时，SNAP和SNAG对FGF2诱导的新生血管形成的抑制率为85%；当给予50μg单剂量时，对CAM中FGF2诱导的血管生成的抑制率为87%。因此，NO供体可能是抑制与人类肿瘤生长、新生血管、眼部和炎症性疾病相关的血管生成的有用工具。
