C-CBL is required for inhibition of angiogenesis through modulating JAK2/STAT3 activity in ROP development.
C-CBL is required for inhibition of angiogenesis through modulating JAK2/STAT3 activity in ROP development.
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DOI：
10.1016/j.biopha.2020.110856
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Chen S;Sun Q;Sun D;Willette-Brown J;Anderson MJ;Gu Q;Lewandoski M;Hu Y;Zhu F;Wei F;Zhang J
近年来，早产儿视网膜病变（ROP）的发病率持续上升。然而，目前治疗方法的疗效仍不尽人意。本研究旨在探究C - CBL在ROP视网膜血管生成中的作用及其作为治疗靶点的潜力。
本研究采用小鼠视网膜微血管内皮细胞（mRMECs）以及诱导的实验性ROP/氧诱导视网膜病变（OIR）小鼠，综合运用分子、细胞方法以及组织病理学方法，来研究C - CBL在血管生成中的作用。对出生后第12天（P12）的OIR小鼠幼崽玻璃体内注射过表达c - Cbl的腺病毒或c - Cbl小干扰RNA（siRNA）。通过视网膜免疫荧光（IF）染色、视网膜铺片以及苏木精 - 伊红（H&E）染色来评估视网膜新生血管形成和无血管状态。
C - CBL以泛素化依赖的方式负向调控JAK2/STAT3/VEGF信号轴，从而抑制新生血管形成。在mRMECs中，siRNA敲低c - Cbl可减少泛素介导的JAK2降解，增加p - JAK2、p - STAT3、VEGF水平以及新生血管形成，而JAK2抑制剂处理可逆转这一现象。在OIR小鼠中，敲低c - Cbl显著增加视网膜中的新生血管（NV）区域，而过表达c - Cbl则抑制视网膜组织中的新生血管形成。
我们发现，C - CBL通过抑制JAK2/STAT3依赖的血管生成，在ROP发展过程的抗新生血管形成中发挥作用。因此，我们的研究结果有力地表明，C - CBL可能是治疗ROP的一个潜在新型治疗靶点。
The incidence of retinopathy of prematurity (ROP) has increased continuously in recent years. However, the therapeutic effects of current treatments still remain undesired. This study aims to investigate the role of C-CBL in retinal angiogenesis in ROP and its potential as a therapeutic target. Mouse retina microvascular endothelial cells (mRMECs) and induced experimental ROP/ oxygen-induced retinopathy (OIR) mice were employed to investigate the role of C-CBL in angiogenesis with combined molecular and cellular approaches, and histopathology methods. OIR mouse pups at postnatal day 12 (P12) were either injected intravitreally with adenovirus overexpressing c-Cbl or c-Cbl siRNA. Retinal neovascularization and avascular status were evaluated by retinal immunofluorescence (IF) staining, whole-mounts and hematoxylin and eosin (H&E) staining. C-CBL inhibits neovascularization by negatively regulating JAK2/STAT3/VEGF signaling axis in a ubiquitination-dependent manner. Knockdown of c-Cbl by siRNA reduced ubiquitin-mediated JAK2 degradation and increased levels of p-JAK2, p-STAT3, VEGF, and neovascularization in mRMECs, which can be reversed by JAK2 inhibitor treatment. While knockdown of c-Cbl significantly increased neovascular (NV) zone in the retinas, c-Cbl overexpression inhibited neovascularization in the retinal tissues in OIR mice. We found that C-CBL is required for anti-neovascularization process in ROP development by inhibiting JAK2/STAT3-dependent angiogenesis. Thus, our finding strongly suggest that C-CBL may be a potential novel therapeutic target for treating ROP.
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影响因子：
7.7
作者：
Zheng Z;Chen H;Ke G;Fan Y;Zou H;Sun X;Gu Q;Xu X;Ho PC
通讯作者：
Ho PC
影响因子：
13.7
作者：
Hartnett, M. Elizabeth
通讯作者：
Hartnett, M. Elizabeth
影响因子：
9.8
作者：
Simmons AB;Bretz CA;Wang H;Kunz E;Hajj K;Kennedy C;Yang Z;Suwanmanee T;Kafri T;Hartnett ME
通讯作者：
Hartnett ME
影响因子：
13.7
作者：
Bressler, Neil M.
通讯作者：
Bressler, Neil M.
DOI：
10.1056/nejmra1208129
发表时间：
2012-12-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hartnett ME;Penn JS
通讯作者：
Penn JS