한빛사논문
- 조회2,488
Abstract
Chang-Hwan Yoon, MD* Young-Eun Choi, MSc* Young Ryun Cha, PhD* Seok-Jin Koh, BSc Jae-il Choi, BSc Tae-Won Kim, BSc Se Joon Woo, MD Young-Bae Park, MD, PhD In-Ho Chae, MD Hyo-Soo Kim, MD, PhD
From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science andTechnology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
*Drs Yoon and Cha and Ms Y-E Choi contributed equally to this work.
Correspondence to : Hyo-Soo Kim, MD, PhD, FAHA, Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Department of Internal Medicine, Seoul National University College of Medicine, 101 DaeHak-ro, JongRo-gu, Seoul 110.744, Seoul, Korea or In-Ho Chae, MD, Cardiovascular Center, Seoul National University Bundang Hospital, 82 Gumiro 173, Bundanggu, 463.707, Seongnam, Republic of Korea.
Abstract
Background: Several mechanisms have been proposed to account for diabetes-induced microvasculopathy (DMV). Although Notch signaling was reported to be affected by glucose metabolism in endothelial cells during developmental angiogenesis, it has not been investigated in vascular remodeling of adult capillaries in relation to diabetes mellitus.
Methods: We induced diabetes mellitus in 8-week-old adult mice by intravenously administering streptozotocin. After 6 weeks, we harvested organs, including retina, heart, and skeletal muscle, and evaluated the capillaries with immunofluorescence and confocal microscopy. We modulated endothelial Notch signaling using chemical inhibitors in wild-type mice or transgenic mice, inducing conditional knockout of Jagged1 or Mib1.
Results: DMV was characterized by capillary remodeling, regression, and decreased density. Notch ligand Jagged1, but not δ-like ligand 4, was markedly increased in endothelial cells of diabetic mice. Using endothelium-specific Jagged1 knockdown mice, we found that blocking Jagged1 prevented DMV even under diabetic conditions. Furthermore, in the inducible endothelium-specific Jagged1 knockdown mice, blocking Jagged1 even at 4 weeks after the establishment of DMV could reverse it, leading to normalization of retinal vasculature. A search for downstream signals revealed that diabetes mellitus decreased the nuclear localization of Notch1 intracellular domain and reduced the expression of VE-cadherin and N-cadherin in endothelial cells. Chemical Notch inhibition phenocopied DMV in normal mice.
Conclusions: Our findings indicate that diabetes mellitus induces Jagged1 overexpression and suppresses Notch signaling in endothelial cells, leading to DMV in adult mice. We conclude that dysregulated intercellular Notch signaling may be a novel mechanism of DMV.
Key Words : capillaries, diabetes complications, diabetes mellitus, intercellular signaling peptides and proteins, pathologic angiogenesis
논문정보
- Research article
- 2016년 07월 (BRIC 등록일 2016-07-25)
- 국내 연구진
- 의약학 > 응용의학
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