2000 Fiscal Year Annual Research Report

神経堤細胞から血管平滑筋細胞への分化機構の解明

Research Project

Project/Area Number	12032205
Research Institution	Kumamoto University
Principal Investigator	栗原裕基熊本大学, 発生医学研究センター, 教授 (20221947)
Keywords	エンドセリン / 神経堤細胞 / 鰓弓 / 平滑筋細胞 / 大血管形成 / dHAND / neuropilin-1 / FGF8
Research Abstract	ET-1-/-マウスでは鰓弓における神経堤由来の大血管平滑筋・骨・軟骨などの間葉系組織に分化、形態形成異常を認めた。ET-1は上皮細胞に、ETA受容体は神経堤由来外胚葉性間葉細胞に発現が見られた。ET-1-/一胚の大血管平滑筋および鰓弓間充織ではdHAND,eHAND,goosecoidなどの転写因子の発現が低下〜消失しており、さらに大血管におけるneuropilin-1の発現が著減していた。dHAND-/-マウスにおいてneuropilin-1の発現が低下していること、neuropilin-1-/-マウスにおいても大血管形成に同様の異常をきたすことから、ET-1→dHAND→neuropilin-1のシグナル経路の存在が明らかになった。 ET-1が神経堤細胞の分化に関与する分子機序を、第1鰓弓Meckel軟骨の形成を中心に解析した。軟骨分化に重要な転写因子Sox9の発現は、マウス胚の第1,2鰓弓で間葉凝集→Meckel軟骨形成に先立って限局的に認められたが、ET-1-/-胚とその鰓弓器官培養においては凝集パターンを作らず、Meckel軟骨形成も認められなかった。マイクロビーズによるET-1添加実験では、ET-1によってはSox9発現は誘導されず、ET-1はSox9自体の発現誘導よりもSox9陽性細胞の凝集に重要と考えられた。一方、正常胚とET-1-/-胚由来の鰓弓器官培養のいずれにおいてもFGF8添加によってSox9の発現が誘導された。鰓弓上皮におけるFGF8の発現パターンにも差はなかった。さらに、抗FGF8中和抗体処理により器官培養におけるSox9発現が阻害された。以上より、ET-1は神経堤細胞から血管平滑筋を含めた間葉系細胞への分化に、HAND,goosecoidなどの転写因子の活性化を介して関与する。血管平滑筋への分化と血管形成においては、ET-1→dHAND→neuropilin-1のシグナル経路が重要と考えられ、SemaphorinIIIやVEGF165との相互作用が今後注目される。さらに、神経堤細胞から軟骨への分化・形態形成においてはFGF8→Sox9のシグナル経路との協調作用が示唆された

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] Kato N: "Evaluation of the poly (ADP-ribose) polymerase gene in human stroke."Atherosclerosis. 148. 345-352 (2000)
[Publications] Imai Y: "Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases."Atherosclerosis. 149. 435-442 (2000)
[Publications] Miyao M: "Association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and osteoporosis in postmenopausal Japanese women."Calcified Tissue Int.. 66. 190-194 (2000)
[Publications] Shindo T: "Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature."Circulation. 101. 2309-2316 (2000)
[Publications] Morita H: "Genetic coronary risk factors in conventionally low-risk patients."Thromb.Haemost.. 84. 137 (2000)
[Publications] Kurihara H: "Role of endothelin-1 in stress response in the central nervous system."Am.J.Physiol.. 279. R515-R521 (2000)
[Publications] Shindo T: "ADAMTS-1 : a metalloproteinase-disintegrin essential for normal growth, fertility and organ morphology and function."J.Clin.Invest.. 105. 1345-1352 (2000)
[Publications] Kato N: "Genetic analysis of the atrial natriuretic peptide in essential hypertension."Clin.Sci.. 98. 251-258 (2000)
[Publications] Sata M: "A Mouse Model of Vascular Injury that Induces Rapid Onset of Medial Cell Apoptosis Followed by Reproducible Neointimal Hyperplasia."J.Mol.Cell.Cardiol.. 32. 2097-2104 (2000)
[Publications] Taniguchi F: "Molecular cloning of the bovine MYOC and induction of its expression in trabecular meshwork cells."Invest.Ophthalmol.Vis.Sci.. 41. 2070-2075 (2000)
[Publications] Imai Y: "Left cervicalaortic arch with aortic coarctation and saccular aneurysm."Jpn.Circ.J.. 64. 544-546 (2000)
[Publications] Morita H: "Homocysteine as a risk factor for restenosis aftercoronary angioplasty."Thromb.Haemost.. 84. 27-31 (2000)
[Publications] Harats D: "Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice."Arterioscler.Thromb.Vasc.Biol.. 20. 2100-2105 (2000)
[Publications] Kato N: "Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese."J.Hypertens.. 18. 1025-1032 (2000)
[Publications] Morita H: "Diet-induced hyperhomocysteinemiaexacerbates neointima formation in rat carotid arteries after baloon injury."Circulation. 103. 133-139 (2001)

2000 Fiscal Year Annual Research Report

神経堤細胞から血管平滑筋細胞への分化機構の解明

Principal Investigator

栗原 裕基 熊本大学, 発生医学研究センター, 教授 (20221947)

Research Products

[Publications] Kato N: "Evaluation of the poly (ADP-ribose) polymerase gene in human stroke."Atherosclerosis. 148. 345-352 (2000)

[Publications] Imai Y: "Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases."Atherosclerosis. 149. 435-442 (2000)

[Publications] Miyao M: "Association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and osteoporosis in postmenopausal Japanese women."Calcified Tissue Int.. 66. 190-194 (2000)

[Publications] Shindo T: "Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature."Circulation. 101. 2309-2316 (2000)

[Publications] Morita H: "Genetic coronary risk factors in conventionally low-risk patients."Thromb.Haemost.. 84. 137 (2000)

[Publications] Kurihara H: "Role of endothelin-1 in stress response in the central nervous system."Am.J.Physiol.. 279. R515-R521 (2000)

[Publications] Shindo T: "ADAMTS-1 : a metalloproteinase-disintegrin essential for normal growth, fertility and organ morphology and function."J.Clin.Invest.. 105. 1345-1352 (2000)

[Publications] Kato N: "Genetic analysis of the atrial natriuretic peptide in essential hypertension."Clin.Sci.. 98. 251-258 (2000)

[Publications] Sata M: "A Mouse Model of Vascular Injury that Induces Rapid Onset of Medial Cell Apoptosis Followed by Reproducible Neointimal Hyperplasia."J.Mol.Cell.Cardiol.. 32. 2097-2104 (2000)

[Publications] Taniguchi F: "Molecular cloning of the bovine MYOC and induction of its expression in trabecular meshwork cells."Invest.Ophthalmol.Vis.Sci.. 41. 2070-2075 (2000)

[Publications] Imai Y: "Left cervicalaortic arch with aortic coarctation and saccular aneurysm."Jpn.Circ.J.. 64. 544-546 (2000)

[Publications] Morita H: "Homocysteine as a risk factor for restenosis aftercoronary angioplasty."Thromb.Haemost.. 84. 27-31 (2000)

[Publications] Harats D: "Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice."Arterioscler.Thromb.Vasc.Biol.. 20. 2100-2105 (2000)

[Publications] Kato N: "Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese."J.Hypertens.. 18. 1025-1032 (2000)

[Publications] Morita H: "Diet-induced hyperhomocysteinemiaexacerbates neointima formation in rat carotid arteries after baloon injury."Circulation. 103. 133-139 (2001)

栗原裕基熊本大学, 発生医学研究センター, 教授 (20221947)