Study of the effects of β-adrenergic receptor agonists and antagonists on pericyte survival in retinopathies : 망막질환에서 베타-아드레날린 수용체 항진제와 길항제가 혈관주위세포 생존에 미치는 영향에 관한 연구

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Jang-Hyuk Yun

의과대학 의학과
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서울대학교 대학원
Diabetic retinopathyRetinopathy of prematurityβ-adrenergic receptor agonistβ-adrenergic receptor antagonistPericyte lossVascular leakageNeovascularization
학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2017. 2. 조정현.
Retinopathy is a disease caused by persistent or severe retinal damage. Diabetic retinopathy (DR) and retinopathy of prematurity (ROP) are representative diseases of retinopathy. DR and ROP are caused by the proliferation of abnormal new blood vessels or upregulation of vascular leakage. Increased expression of angiogenic factors, such as vascular endothelial growth factor (VEGF), or retinal pericyte loss has been demonstrated to lead to vascular leakage and neovascularization in DR or ROP. Thus, the prevention of pericyte loss is a potential target for the treatment of retinopathy. An increasing body of evidence suggests the importance of β-adrenergic receptor signaling in pericyte biology. For example, the loss of sympathetic neurotransmission leads to pericyte loss in the retinas of mouse and rat. In this study, I investigated the effects of β-adrenergic receptor agonists and antagonists on pericyte loss in retinal diseases. I demonstrated that β-adrenergic receptor agonists (β-agonists) inhibited pericyte apoptosis induced by high glucose, Ang2, and TNF-α, which are increased in diabetic retinas. β-Agonists also increased pericyte proliferation under high glucose conditions. Conversely, nonselective β-adrenergic receptor antagonists (nonselective β-antagonists), rather induced pericyte apoptosis and reduced pericyte proliferation under hypoxic conditions. β-agonists did not induce any changes in endothelial cell survival and proliferation and β-antagonists only induced a slight decrease of endothelial cell proliferation. Both β-agonists and β-antagonists were involved in the survival and proliferation of pericyte through the PI3K/AKT and MAPK/ERK pathways. Interestingly, β2-agonists were more effective in the induction of pericyte survival and proliferation than β1-agonists
this resulted from higher expression of the β2-adrenergic receptor than the β1-adrenergic receptor in pericytes under high glucose conditions. Furthermore, β2-agonists effectively prevented pericyte loss and vascular leakage in a mouse model of DR. On the other hand, β-antagonists aggravated vascular leakage and neovascularization by the promotion of pericyte loss in oxygen-induced retinopathy (OIR). Together, these results suggested that β2-agonists effectively attenuated pericyte loss in DR by the promotion of pericyte survival and proliferation and may be a potential therapeutic agent for the prevention of retinal vascular leakage in DR. On the other hand, β-antagonists were not appropriate for the treatment of ROP by the induction of pericyte loss, and that administration to patients should be carefully monitored.
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Ph.D. / Sc.D._의학과)
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