2005 Fiscal Year Final Research Report Summary
Basic Research of Pulmonary Angiogenesis fir the Patients with Complicated Cyanotic Congenital Heart Diseases.
| Project/Area Number |
16591047
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
HAMAOKA Kenji Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Professor, 医学研究科, 教授 (60189602)
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| Co-Investigator(Kenkyū-buntansha) |
SHIRAISHI Isao Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Assistant Professor, 医学研究科, 講師 (80295659)
TAKAMATSU Tetsuro Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Professor, 医学研究科, 教授 (40154900)
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| Project Period (FY) |
2004 – 2005
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| Keywords | VEGF / Flk-1 / Flt-1 / angiogenesis / vasculogenesis / lung / mouse / embryo |
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| Research Abstract |
In lung tissues, VEGF is diffusely expressed throughout embryonic stages, whereas development of vascular endothelial cells is not uniform. Noting the signaling properties of the two VEGF receptors, we hypothesized that Flk-1 and Flt-1 regulate embryonic development of lung vasculature. Experiment1) To test this concept, we studied experimental inhibition of Flk-1 and Flt-1 during the mouse embryonic pulmonary vascular development. Treatment of cultured lung buds (E11.5) with antisense oligonucleotides complementary to Flk-1 resulted in insufficient branching of capillaries, impaired proliferation and promoted apoptosis of endothelial cells, and decreased ephrin B2-positive arterial cell lineage. In contrast, inhibition of Flt-1 with antisense oligonucleotides promoted branching of capillaries, enhanced proliferation of endothelial cells, and increased ephrin B2-positive arterial cell lineage. Interestingly, inhibition of Flt-1 in lung buds promoted Flk-1 expression but inhibition of F
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lk-1 did not enhance Flt-1 expression. These results suggest that the two VEGF receptors, not merely VEGF itself, spatiotemporally regulate pulmonary vascular development and that the transition from Flk-1 to Flt-1 is a key process to organize pulmonary capillary networks. Experiment2)ICR pregnant mice were intraperitoneally injected with 15.0 mg/kg of all-trans retinoic acid (ATRA) dissolved in dimethylsulfoxide on ED 6.5. Development of cardiopulmonary system was analyzed by dissecting microscopy, H&E staining and confocal observation using phalloidin and PECAM-1 antibody. Heart anomalies after maternal administration of RA included right (25%) and left isomerism (<10%). Right isomeric heart was associated with transposition of great artery (66%) and common atrioventricular canal (50%). Histologic al observation revealed undifferentiated pulmonary epithelial cells and disrupted cell polarity with sparse mesenchyme at E13.5. Mesenchymal cells were, in turn, overcrowded after E14.5. PECAM-1-positive vascular endothelial cells constituted capillary networks at E18.5, however, they did not form normal alveolar-capillary interface which is characterized by thin alveolar septa. These findings suggest that maternal administration of RA induced an impaired development of alveolar system and complicated heart anomalies associated with right or left isomerism. Less
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