1998 年度実績報告書

血管構築の分子機構

研究課題

研究課題/領域番号	09281101
研究機関	東北大学
研究代表者	佐藤靖史東北大学, 加齢医学研究所, 教授 (50178779)
研究分担者	藤原敬己国立循環器病センター研究所, 循環器形態部長 (10190092) 月田承一郎京都大学, 大学院・医学研究科, 教授 (50155347) 三井洋司生命工学工業技術研究所, 首席研究官西川伸一京都大学, 大学院・医学研究科, 教授 (60127115) 渋谷正史東京大学, 医科学研究所, 教授 (10107427)
キーワード	VEGF / Flt-1 / KDR / Flt-4 / クローディン / PECAM-1
研究概要	VEGF-AはFlt-1(VEGF1型受容体)とKDR/Flk-1(VEGF2型受容体)結合すると、Flt-1/Flt-1のホモダイマー、Flt-1KDRのへテロダイマー、KDR/KDRのホモダイマーを形成する。このうちKDR/KDRとFlt-KDRは、内皮細胞の増殖、細胞接着、転写因子ETS-1の発現を調節し、Flt-1/Flt-1はアクチンの再構成による運動性を調節すること、さらに前者のシグナルはPKC-ERK1/2、後者のシグナルはp38 MAPKによって伝達されることを明らかにした(佐藤)。Flt-1遺伝子は胎生期の血管新生に必須であるが、キナーゼドメインのみを欠失させた部分ターゲッティングマウスでは、胎生期の血管形成は正常に起こることを明らかにした。また、KDRのみに結合するVEGF-Eを同定した(澁谷)。VEGF-CやVEGF-Dを結合するFlt-4(VEGF3型受容体)の結合阻害抗体を作成し、本来リンパ管で機能すると考えられていたFlt-4が血管新生の過程で血管内皮にも発現し、その結合を阻害すると血管新生が抑制されることを明らかにした(西川)。ヒト臍帯静脈内皮細胞由来細胞株の無血清培養系を確立し、培養上清中の分泌蛋白について解析を進めた(三井)。タイトジャンクションを構成する新しい4回膜貫通型蛋白質クローディンを同定することに成功した。この蛋白質には、いわゆるアイソタイプが多く存在し、このうちクローディン5が血管内皮に特異的に発現しているらしいことを明らかにした(月田)。流れ刺激を受けると内皮細胞のPECAM-1はc-srcによってチロシンリン酸化され、さらに下流のMAPキナーゼへとシグナルが伝達されることを明らかにした(藤原)。

研究成果
(20件)

すべてその他

すべて文献書誌 (20件)

[文献書誌] Oda,N.,Abe,M.,and Sato,Y.: "ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin b3." J.Cell.Physiol.178. 121-132 (1999)
[文献書誌] Tanaka,K.,Oda,N.,Iwasaka,C.,Abe,M.,and Sato,Y.: "Induction of Ets-1 in endothelial cells during re-endothelialization after denuding injury." J.Cell.Physiol.176. 235-244 (1998)
[文献書誌] Abe,M.,Oda,N.,and Sato,Y.: "Cell-associated activation of latent transforming growth factor-b by calpain." J.Cell.Physiol.174. 186-193 (1998)
[文献書誌] Hiratsuka,S.,Minowa,O.,Kuno,J.,Noda,T.,and Shibuya,M.: "Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice." Proc.Natl.Acad.Sci.USA. 95. 9349-9354 (1998)
[文献書誌] Luo,J.-C.,Yamaguchi,S.,Shinkai,A.,Shitara,K.,and Shibuya,M.: "Significant Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor in Mouse Ascites Tumors." Cancer Res.58. 2652-2660 (1998)
[文献書誌] Hirashima M,Kataoka M,Nishikawa S,Matsuyoshi M,and Nishikawa SI: "Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis." Blood. 93. 1253-1263 (1999)
[文献書誌] Ogawa M,Kizumoto M,Nishikawa S,Fujimoto T,Kodama H,Nishikawa SI: "Expression of α4-integrin defines the earliest percursor of hematopoietic cell lineage diverged from endothelial cells." Blood. 93. 1168-1177 (1999)
[文献書誌] Nishikawa SI,Nishikawa S,Kawamoto H,Yoshida H,Kizumoto M,Kataoka H,and Katsura Y: "In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos." Immunity. 8. 761-769 (1998)
[文献書誌] Nishikawa SI,Nishikawa S,Kataoka H,Matsuyoshi N,and Kodama H: "Progressive lineage analysis by cell sorting and culture identifies Flk1^+VE-cadherin^+cells as the diverging point of endothelial and hematopoietic lineages." Development. 125. 1747-1757 (1998)
[文献書誌] Yoshida H,Takakura N,Hirashima M,Kataoka H,Tsuchida K,Nishikawa S and Nishikawa SI: "Hematopoietic tissues as a playground of receptor tyrosine kinases of the PDGF receptor family." Dev.Compar.Immunol.22. 321-332 (1998)
[文献書誌] T.Sugihara,R.Wadhwa,S.C.Kaul and Y.Mitsui: "A Novel Altematively Spliced From Of Murine Vascmlar Endothelial Growth Factor,VEGF115." J.Biol.Chem.273. 3033-3038 (1998)
[文献書誌] J.Fukami-Kobayashi and Y.Mitsui: "The Regulation of Cyclin D1 Expression in Senescent Human Fibroblasts." Exp.Cell Res.241. 435-444 (1998)
[文献書誌] R.Wadhwa,S.Takano,M.Robert,A.Yoshida,H.Nomura,R.R.Rsddel,Y.Mitsui and S.C.Kaul: "Inactivation of Tumor Suppressor p53 by Mot-2,hsp70 Family Member." J.Biol.Chem.273. 29586-29591 (1998)
[文献書誌] Furuse,M.,Sasaki,H.,Fujimoto,K.,and Tsukita,Sh: "A single gene product,claudin-1 or -2,reconstitutes tight junction strands and recruits occludin in fibroblasts." J.Cell Biol.143. 391-401 (1998)
[文献書誌] Furuse,M.,Fujita,K.,Hiiragi,T.,Fujimoto,K.,and Tsukita,Sh.: "Claudin-1 and -2: Novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin." J.Cell Biol.141. 1539-1550 (1998)
[文献書誌] Saitou,M.,Fujimoto,K.,Doi,Y.,Itoh,M.,Fujimoto,T.,Furuse,M.,Takano,H.,Noda,T. and Tsukita,Sh.: "Occludin-deficient embryonic stem cells can diferentiate into polarized epithelial cells bearing tight junctions." J.Cell Biol.141. 397-408 (1998)
[文献書誌] Onishi,H.,M.F.Morales,S.Kojima,K.Katoh and K.Fujiwara.: "Functionaltransitions in myosin: Formation of a critical salt-bridge and transmissionof effects to the sensitive tryptophan." Proc.Natl.Acad.Sci.USA. 95. 6653-6658 (1998)
[文献書誌] Ochi,H.,N.Kume,E.Nishi,H.Moriwaki,M.Masuda,K.Fujiwara and T.Kita.: "Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 induced by lysophosphatyidylcholine in cultured endothelialcells." Biochem.Biophys.Res.Comm.243. 862-868 (1998)
[文献書誌] Katoh,K.,Y.Kano,M.Masuda and K.Fujiwara.: "Isolation and contractionof the stress fiber." Mol.Biol.Cell. 9. 1919-1938 (1998)
[文献書誌] 佐藤靖史: "血管新生の最前線" 羊土社, 174 (1999)

1998 年度 実績報告書

血管構築の分子機構

研究代表者

佐藤 靖史 東北大学, 加齢医学研究所, 教授 (50178779)

研究成果

[文献書誌] Oda,N.,Abe,M.,and Sato,Y.: "ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin b3." J.Cell.Physiol.178. 121-132 (1999)

[文献書誌] Tanaka,K.,Oda,N.,Iwasaka,C.,Abe,M.,and Sato,Y.: "Induction of Ets-1 in endothelial cells during re-endothelialization after denuding injury." J.Cell.Physiol.176. 235-244 (1998)

[文献書誌] Abe,M.,Oda,N.,and Sato,Y.: "Cell-associated activation of latent transforming growth factor-b by calpain." J.Cell.Physiol.174. 186-193 (1998)

[文献書誌] Hiratsuka,S.,Minowa,O.,Kuno,J.,Noda,T.,and Shibuya,M.: "Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice." Proc.Natl.Acad.Sci.USA. 95. 9349-9354 (1998)

[文献書誌] Luo,J.-C.,Yamaguchi,S.,Shinkai,A.,Shitara,K.,and Shibuya,M.: "Significant Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor in Mouse Ascites Tumors." Cancer Res.58. 2652-2660 (1998)

[文献書誌] Hirashima M,Kataoka M,Nishikawa S,Matsuyoshi M,and Nishikawa SI: "Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis." Blood. 93. 1253-1263 (1999)

[文献書誌] Ogawa M,Kizumoto M,Nishikawa S,Fujimoto T,Kodama H,Nishikawa SI: "Expression of α4-integrin defines the earliest percursor of hematopoietic cell lineage diverged from endothelial cells." Blood. 93. 1168-1177 (1999)

[文献書誌] Nishikawa SI,Nishikawa S,Kawamoto H,Yoshida H,Kizumoto M,Kataoka H,and Katsura Y: "In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos." Immunity. 8. 761-769 (1998)

[文献書誌] Nishikawa SI,Nishikawa S,Kataoka H,Matsuyoshi N,and Kodama H: "Progressive lineage analysis by cell sorting and culture identifies Flk1^+VE-cadherin^+cells as the diverging point of endothelial and hematopoietic lineages." Development. 125. 1747-1757 (1998)

[文献書誌] Yoshida H,Takakura N,Hirashima M,Kataoka H,Tsuchida K,Nishikawa S and Nishikawa SI: "Hematopoietic tissues as a playground of receptor tyrosine kinases of the PDGF receptor family." Dev.Compar.Immunol.22. 321-332 (1998)

[文献書誌] T.Sugihara,R.Wadhwa,S.C.Kaul and Y.Mitsui: "A Novel Altematively Spliced From Of Murine Vascmlar Endothelial Growth Factor,VEGF115." J.Biol.Chem.273. 3033-3038 (1998)

[文献書誌] J.Fukami-Kobayashi and Y.Mitsui: "The Regulation of Cyclin D1 Expression in Senescent Human Fibroblasts." Exp.Cell Res.241. 435-444 (1998)

[文献書誌] R.Wadhwa,S.Takano,M.Robert,A.Yoshida,H.Nomura,R.R.Rsddel,Y.Mitsui and S.C.Kaul: "Inactivation of Tumor Suppressor p53 by Mot-2,hsp70 Family Member." J.Biol.Chem.273. 29586-29591 (1998)

[文献書誌] Furuse,M.,Sasaki,H.,Fujimoto,K.,and Tsukita,Sh: "A single gene product,claudin-1 or -2,reconstitutes tight junction strands and recruits occludin in fibroblasts." J.Cell Biol.143. 391-401 (1998)

[文献書誌] Furuse,M.,Fujita,K.,Hiiragi,T.,Fujimoto,K.,and Tsukita,Sh.: "Claudin-1 and -2: Novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin." J.Cell Biol.141. 1539-1550 (1998)

[文献書誌] Saitou,M.,Fujimoto,K.,Doi,Y.,Itoh,M.,Fujimoto,T.,Furuse,M.,Takano,H.,Noda,T. and Tsukita,Sh.: "Occludin-deficient embryonic stem cells can diferentiate into polarized epithelial cells bearing tight junctions." J.Cell Biol.141. 397-408 (1998)

[文献書誌] Onishi,H.,M.F.Morales,S.Kojima,K.Katoh and K.Fujiwara.: "Functionaltransitions in myosin: Formation of a critical salt-bridge and transmissionof effects to the sensitive tryptophan." Proc.Natl.Acad.Sci.USA. 95. 6653-6658 (1998)

[文献書誌] Ochi,H.,N.Kume,E.Nishi,H.Moriwaki,M.Masuda,K.Fujiwara and T.Kita.: "Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 induced by lysophosphatyidylcholine in cultured endothelialcells." Biochem.Biophys.Res.Comm.243. 862-868 (1998)

[文献書誌] Katoh,K.,Y.Kano,M.Masuda and K.Fujiwara.: "Isolation and contractionof the stress fiber." Mol.Biol.Cell. 9. 1919-1938 (1998)

[文献書誌] 佐藤靖史: "血管新生の最前線" 羊土社, 174 (1999)

1998 年度実績報告書

佐藤靖史東北大学, 加齢医学研究所, 教授 (50178779)