2004 Fiscal Year Final Research Report Summary
Moleculo-Pathological studies on intracellular cross-talk signal in angiogenic process.
| Project/Area Number |
14370078
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
NAKAGAWA Kazunori KYUSHU UNIVERSITY, Graduate School of Medical Science, assistant professor, 大学院・医学研究院, 講師 (50217668)
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| Co-Investigator(Kenkyū-buntansha) |
SUEISHI Katsuo GKYUSHU UNIVERSITY, Graduate School of Medical Science, Professor, 大学院・医学研究院, 教授 (70108710)
YONEMITSU Yoshikazu KYUSHU UNIVERSITY, Graduate School of Medical Science, Associate Professor, 大学院・医学研究院, 助教授 (40315065)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Endothelial Cell / cross-talk sianal / Gene Transfer / Angiogenesis / Vascular Remodeling / Gene Therapy |
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| Research Abstract |
The mechanism of intracellular crosstalk of angiogenic factors and its patho-physiological role in physiological and pathological angiogenesis remain unclear. To elucidate this time-dependent and spatial angiogenic crosstalk and to establish the novel and effective therapy on the basis of our evidences obtained for positive and negative angiogenic diseases, we studied the molecular mechanisms of angiogenesis/vasculogenesis, and we have got the following results.
(1)Time-dependent and spatial hierarchy of angiogenic factors durhg molecular and cellular crosstalks :
FGF 2-induced angiogenesis is mediated by MEK in early phase and p70^<s6k>, and Ras/PDGF in late phase of VEGF and HGF expressions. In murine tumor transplantation models, p70^<s6k> and Ras/PDGF pathways were important enhancers of VEGF-A and other angiogenic factors expressed by not only stromal mesenchymal cells but also tumor cells. In addition, FGF-2 gene transferred to ischemic limbs could induce a well harmonizing and fun
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ctional angiogeness partly as a hierarchical enhancer of other angiogenic factors such as VEGF,VEGF-C,VEGF-D,HGF and PDGF.
(2)Atherosderosis and infra-neohtimal angiogenesis :
The number of VEGF-C-positive cells correlate with the degree of atherosclerosis and the number of newly formed vessels in atherosclerotic intima. Increased expression and activity of VEGF are essential in the development of experimental restenosis after intraluminal catheterization by recruiting monocytes/macrophages. There were two disribution patterns of pigment epithelium derived factor (PEDF) in atherosclerotic intima of human coronary arteries. The difference of distribution pattern is closey related to intimal angiogenesis pattern. Moreover, significant inverse correlation between the number of IL-10-positive cells expressed mainly by macrophages and the number of lymphocytes infiltrated in the same areas. These findings suggest that VEGF,VEGF-C,PEDF and IL-10 play important roles in progression of atherosclerosis.
(3)Biological characteristics of our novel gene transfer vectors and their therapeutic implications :
Simian immunodeficiency virus(SIV) vector is efficiently and safely applicable to retinal gene transfer by assessing the transgene expression activity, retinal function and histologies over about 1-year period following subretinal injection of target genes into adult rat retinas. We also demonstrated that neuroprotective gene therapy using SIV-PEDF could be protective from retinal degeneration and functional loss in mice with retintis pigmentosa. These data indicate that SIV-mediated stable gene expression might be a high potential tool for gene therapy. Therapeutic angiogeness using SeV hFGF-2 may be applicable for ischemic organs such as limbs and coronary insuficiency. In porcine model of myocardial infarction, we demonstrated that SeV-FGF-2 could suppress the cardiac ischemia, rupture and heart failure, by using a novel catheter for gene transfer to myocardium from ventricular lumen.
These findings suggest that well harmonized cellular and spatial closstalks/feedback loops of angiogenic factors play important roles in angiogenesis. Rhexis of the harmonized balance leads to several angiogenic diseases. Our novel gene transfer vectors could be expected to be powerful therapeutic tools. Less
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Research Products
(36 results)
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[Journal Article] The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization.2004
Author(s)
Miyoshi K, Wakioka T, Nishinakamura H, Kamio M, Yang L, Inoue M, Hasegawa M, Yonemitsu Y, Komiya S, Yoshimura A
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Journal Title
Oncogene 23(33)
Pages: 5567-5576
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats.2004
Author(s)
Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K, Takeshit A
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Journal Title
Circ Res 94(3)
Pages: 385-393
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Blockade of Vascular Endothelial Growth Factor Suppresses Experimental Restenosis After Intraluminal Injury by Inhibiting Recruitment of Monocyte Lineage Cells.2004
Author(s)
Ohtani K, Egashira K, Hiasa KI, Zhao Q, Kitamoto S, Ishibashi M, Usui M, Inoue S, Yonemitsu Y, Sueishi K, Sata M, Shibuya M, Sunagawa K
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Journal Title
Circulation 110(16)
Pages: 2444-2452
Description
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[Journal Article] Essential Role of PDGFR{alpha}-p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo. Role of PDGFR{alpha} During Angiogenesis.2004
Author(s)
Tsutsumi N, Yonemitsu Y, Shikada Y, Onimaru M, Tanii M, Okano S, Kaneko K, Hasegawa M, Hashizume M, Maehara Y, Sueishi K
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Journal Title
Circ Res. 94
Pages: 1186-1194
Description
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[Journal Article] Recombinant Sendai virus vectors for activated T lymphocytes.2003
Author(s)
Okano S, Yonemitsu Y, Nagata S, Sata S, Onimaru M, Nakagawa K, Tomita Y, Kishihara K, Hashimoto S, Nakashima Y, Sugimachi K, Hasegawa M, Sueishi K
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Journal Title
Gene Ther 10(16)
Pages: 1381-1391
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats.2003
Author(s)
Miyazaki M, Ikeda Y, Yonemitsu Y, Goto Y, Sakamoto T, Tabata T, Ueda Y, Hasegawa M, Tobimatsu S, Ishibashi T, Sueishi K
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Journal Title
Gene Ther 10(17)
Pages: 1503-1511
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Simian immunodeficiency virus-based lentivirus vector for retinal gene transfer : a preclinical safety study in adult rats.2003
Author(s)
Ikeda Y, Ikeda Y, Goto Y, Yonemitsu Y, Miyazaki M, Sakamoto T, Ishibashi T, Tabata T, Ueda Y, Hasegawa M, Tobimatsu S, Sueishi K
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Journal Title
Gene Ther 10(14)
Pages: 1161-1169
Description
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[Journal Article] Functional role of Egr-1 mediating VEGF-induced tissue factor expression in the retinal capillary endothelium.2002
Author(s)
Sassa Y, Hata Y, Murata T, Yamanaka I, Honda M, Hisatomi T, Fujisawa K, Sakamoto T, Kubota T, Nakagawa K, Sueishi K, Ishibashi T
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Journal Title
Graefes Arch Clin Exp Ophthalmol 240(12)
Pages: 1003-1010
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Angiogenic gene therapy for experimental critical limb ischemia : acceleration of limb loss by overexpression of vascular endothelial growth factor 165 but not of fibroblast growth factor-2.2002
Author(s)
Masaki I, Yonemitsu Y, Yamashita A, Sata S, Tanii M, Komori K, Nakagawa K, Hou X, Nagai Y, Hasegawa M, Sugimachi K, Sueishi K
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Journal Title
Circ Res 90(9)
Pages: 966-973
Description
「研究成果報告書概要(欧文)」より
