Molecular mechanism of vascular formation

血管形成的分子机制

• 批准号: 09281101
• 负责人: SATO Yasufumi
• 金额: $ 127.87万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas (A)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09281101/
• 关键词: Ets-1; Apoptosis; VEGF; Signal Transduction; ES Cell; differentiation; Claudin-5; Telomerase; Ets-1; HEX; Flt-1; KDR; マウスES細胞; Flk-1陽性細胞; クローディン-5; PECAM-1; Flt-4; クローディン; VEGF様遺伝子; タイトジャンクション; SH-PTP2

(1) Transient overexpression of transcription factor Ets1 promoted apoptosis of endothelial cells (Ecs). Ets1 increased expression of pro-apoptotic Bid, cytochrome p450, caspase-4, p27 and p21 more than 2 fold, while it decreased expression of anti-apoptotic DAD-1, AXL, Cox-2, IAP-2, and MDM-2 less than 0. 5 fold in Ecs. (2) The signal transduction pathway of VEGF appeared to be different between ECs of large vessels and small vessels. Especially, Ras played an important role in ECs of small vessels. (3) Transgenic mouse experiment revealed that VEGF-E, a new member of VEGF family, promoted angiogenesis without any evidences of vascular permeability. (4) Autophosphorylation sites of VEGFR-2 (KDR) were determined to be 1175Y and 1214Y. Carboxyl-terminal SH2 domain of PLC-γ bound to phosphorylated 1214Y, which was indispensable for the MAPK activation and augmented DNA synthesis. (5) MadCAM-1 was specifically expressed in venous ECs in the early embryonic stage. BMP-4 increased the number of MadCAM-1 positive venous ECs. (6) GFP-tagged genes were stably introduced into mouse embryonic stem (ES) cells. Time-rap video system was established to analyze the differentiation of ES cells and the expression pattern of GFP-tagged genes. (7) Target destruction of claudin-5, and EC-specific claudin, was established. (8) Human TERT gene and SV40 T antigen gene were introduced into human umbilical vein ECs (HUVECS). The table transfectants exhibited the prolongation of cell-division capability and were suggested to produce a novel autocrine growth factor.

（1）转录因子ETS1的瞬时过表达促进了内皮细胞（EC）的凋亡。 ETS1增加了凋亡BID的表达，细胞色素P450，caspase-4，P27和P21超过2倍，而抗凋亡DADDAD DAD DADED-1，AXL，COX-2，IAP-2，IAP-2和MDM-2的表达降低了ECS中的0。5倍。 （2）VEGF的信号转导途径在大容器和小血管的EC之间似乎有所不同。特别是，RAS在小型船只的EC中发挥了重要作用。 （3）转基因小鼠实验表明，VEGF家族的新成员VEGF-E促进了血管生成，而没有任何血管通透性的证据。 （4）VEGFR-2（KDR）的自磷酸化位点确定为1175y和1214y。 PLC-γ的羧基末端SH2结构域与磷酸化的1214Y结合，这对于MAPK激活和增强的DNA合成是必不可少的。 （5）MADCAM-1在早期胚胎阶段在静脉EC中特别表达。 BMP-4增加了MADCAM-1阳性静脉EC的数量。 （6）将GFP标记的基因稳定地引入小鼠胚胎（ES）细胞中。建立了时间说唱视频系统，以分析ES细胞的分化和GFP标记基因的表达模式。 （7）建立了Claudin-5和EC特异性Claudin的目标破坏。 （8）将人类TERT基因和SV40 T抗原基因引入人脐静脉EC（HUVEC）。表变换物表现出延长细胞分割能力，并建议产生一种新型的自分泌生长因子。

项目成果

Sato,Y., et al.: "Signal transduction and transcriptional regulation of angiogenesis."Adv.Exp.Med.Biol.. 476. 109-115 (2000)

Sato,Y., et al.：“血管生成的信号转导和转录调节”。Adv.Exp.Med.Biol.. 476. 109-115 (2000)

Tanaka, Y., et al.: "Endothelin-1 is involved in the growth promotion of vascular smooth muscle cells by hyaluronic acid"Int.J.Cardiol.. 76. 39-47 (2000)

Tanaka, Y., et al.：“Endothelin-1 参与透明质酸对血管平滑肌细胞的生长促进”Int.J.Cardiol.. 76. 39-47 (2000)

Tanaka M., et al.: "Expression of the 37-kDa laminin binding protein in murine lung tumor cell correlates with tumor angiogenesis."Cancer Lett.. 153. 161-168 (2000)

Tanaka M. 等人：“鼠肺肿瘤细胞中 37-kDa 层粘连蛋白的表达与肿瘤血管生成相关。”Cancer Lett.. 153. 161-168 (2000)

Tanaka, k., et al.: "Roles of ERK1/2 and p38 MAP kinase in the signal transduction of bFGF in endothelial cells during angiogenesis"Jpn. J. Cancer Res.. 90. 647-654 (1999)

Tanaka, k., et al.：“ERK1/2 和 p38 MAP 激酶在血管生成过程中内皮细胞 bFGF 信号转导中的作用”Jpn。

Niida, S., et al.: "Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption"J. Exp. Med.. 190. 293-298 (1999)

Niida, S., 等人：“血管内皮生长因子可以替代巨噬细胞集落刺激因子来支持破骨细胞骨吸收”J.