Tamura Kazuhiro, Hashimoto Keisuke, Suzuki Kenta, Yoshie Mikihiro, Kutsukake Masahiko, Sakurai Toshihiro
Department of Endocrine Pharmacology, Tokyo University of Pharmacy & Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo, 192-0392, Japan.
Eur J Pharmacol. 2009 May 21;610(1-3):61-7. doi: 10.1016/j.ejphar.2009.01.045. Epub 2009 Feb 5.
Insulin-like growth factor binding protein-7 (IGFBP7) and vascular endothelial growth factor (VEGF) are expressed in vascular endothelial cells in several tumor types. In this study, we examined the effect of IGFBP7 on VEGF-induced tube formation in cultured human umbilical vein endothelial cells (HUVECs) and its potential action in the modulation of VEGF signaling in vascular cells. IGFBP7 treatment suppressed VEGF-induced tube formation, proliferation, and the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) 1/2 in HUVECs. IGFBP7 attenuated VEGF-enhanced cyclooxygenase (COX)-2 and VEGF mRNA expression, and prostaglandin E(2) secretion. Knocking down endogenous IGFBP7 enhanced COX-2 and VEGF mRNA expression. A significant increase in IGFBP7-induced caspases was not observed in the presence of VEGF. These findings indicate that IGFBP7 can modulate the stimulatory effect of VEGF on angiogenesis by interfering with VEGF expression as well as VEGF signaling and not by inducing apoptosis.
胰岛素样生长因子结合蛋白7（IGFBP7）和血管内皮生长因子（VEGF）在多种肿瘤类型的血管内皮细胞中表达。在本研究中，我们检测了IGFBP7对培养的人脐静脉内皮细胞（HUVECs）中VEGF诱导的管腔形成的影响及其在调节血管细胞中VEGF信号传导方面的潜在作用。IGFBP7处理可抑制HUVECs中VEGF诱导的管腔形成、增殖以及丝裂原活化蛋白激酶激酶（MEK）和细胞外信号调节激酶（ERK）1/2的磷酸化。IGFBP7减弱了VEGF增强的环氧化酶（COX）-2和VEGF mRNA表达以及前列腺素E2分泌。敲低内源性IGFBP7可增强COX-2和VEGF mRNA表达。在有VEGF存在的情况下，未观察到IGFBP7诱导的半胱天冬酶显著增加。这些发现表明，IGFBP7可通过干扰VEGF表达以及VEGF信号传导而非诱导细胞凋亡来调节VEGF对血管生成的刺激作用。
