Brain-derived neurotrophic factor inducing angiogenesis through modulation of matrix-degrading proteases

作     者：SUN Chun-yan HU Yu WANG Hua-fang HE Wen-juan WANG Ya-dan WU Tao 

作者机构：Institute of Hematology Union Hospital Tongji Medical CollegeHuazhong University of Science and Technology Wuhan 430022China 

出 版 物：《Chinese Medical Journal》 (中华医学杂志（英文版）)

年 卷 期：2006年第119卷第7期

页      面：589-595页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：This study was supported by a grant from the Youth Talent Foundation of Hubei Province (No. 2003ABB017) 

主　　题：brain-derived neurotrophic factor angiogenesis extracellular proteolytic enzyme 

摘      要：Background Recent studies have proved that brain-derived neurotrophic factor （BDNF） possesses angiogenic activity in vitro and in vivo. However, the proangiogenic mechanism of BDNF has not yet been provided with enough information. To explore the proangiogenic mechanism of BDNF, we investigated the effects of BDNF on extracellular proteolytic enzymes, including matrix metalloproteinases （MMPs） and serine proteases, particularly the urokinase-type plasminogen activator （uPA）-plasmin system in human umbilical vein endothelial cells （HUVECs） model. Methods Tube formation assay was performed in vitro to evaluate the effects of BDNF on angiogenesis. The HUVECs were treated with various concentrations of BDNF （25-400 ng/ml） for different （6-48 hours）, reverse transcriptase-polymerase chain reaction （RT-PCR） was used to assay MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNA in HUVECs, and the conditioned medium was analyzed for MMP and uPA activity by gelatin zymography and fibrin zymography, respectively, uPA, plasminogen activator inhibitor （PAI）-1, tissue inhibitors of metalloproteinase （TIMP）-1, and TIMP-2 were quantified by western blotting analysis. Results BDNF elicited robust and elongated angiogeneis in two-dimensional cultures of HUVECs in comparison with control. The stimulation of serum-starved HUVECs with BDNF caused obvious increase in MMP-2 and MMP-9 mRNA expression and induced the pro-MMP-2 and pro-MMP-9 activation without significant differences in proliferation. However, BDNF had no effect on TIMP-1 and TIMP-2 production. BDNF increased uPA and PAI-1 production in a dose-dependent manner. Maximal activation of uPA and PAI-1 expression in HUVECs was induced by 100 ng/ml BDNF, while effects of 200 ng/ml and 400 ng/ml BDNF were slightly reduced in comparison with with those of 100 ng/ml. Protease activity for uPA was also increased by BDNF in a dose-dependent manner. BDNF also stimulated uPA and PAI-1 production beyond that in control cultures in a time-dependent man