S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
Hyperglycemia-induced Jagged 1 overexpression in endothelial cells causes retinal capillary regression in a murine model of diabetes mellitus
혈관내피세포에서 고농도 당에 의한 Jagged1 발현 증가와 당뇨병성 혈관병증의 병인기전에 관한 연구
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2016. 8. 김효수.
- Introduction: Regulation of vascular morphogenesis (sprouting, branching, lumenization, regression) by Notch signaling has been well characterized during vascular development. In adult mature vasculature, resting endothelial cells (ECs) also retain their growth potential that is activated under certain circumstances, but less is known about the maintenance mechanism of endothelial homeostasis.
Methods: We developed an in vitro model of human angiogenesis. Human ECs and smooth muscle cells (SMCs) in spheroid were co-cultivated on SMC monolayer under high glucose or control conditions.
For in vivo loss-of-function studies, we used both EC-specific Jagged1 (Jag1) heterozygous deficient mice (Tie2-Cre+
Jag1flox/+) and ECs-specific inducible Jag1 deficient mice (Tie2-CreERT2+
Results: Using the in vitro angiogenesis model, we observed high glucose-induced abnormal angiogenesis characterized by increased sprouting and branching points, decreased vascular diameter and length, and destabilization of the tubes. As the underlying mechanism, we identified the PKC- and NF-κB-dependent upregulation of Jag1 in ECs under high glucose condition.
Increased expression of Jag1 was also observed in retinal ECs of streptozotocin-induced diabetic model. We confirmed attenuation of hyperglycemia-induced retinal vascular abnormalities in EC-specific Jag1 deletion mice.
Conclusions: We found that increased expression of Jag1 might be a mechanism of diabetic microvasculopathy. Correction of the pathologic angiogenesis by modulating the aberrant signaling in the present study highlighted a future direction of treatment of diabetic vasculopathy other than glucose control.