eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin.
eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin.
复制标题
eNOS通过c-Src激活和VE-钙粘蛋白酪氨酸磷酸化诱导的视网膜病变血管屏障破坏
DOI：
10.7554/elife.64944
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发表时间：
2021-04-28
期刊：
影响因子：
7.7
通讯作者：
Claesson-Welsh L
中科院分区：
文献类型：
--
作者：
Ninchoji T;Love DT;Smith RO;Hedlund M;Vestweber D;Sessa WC;Claesson-Welsh L
缺氧和随之产生的血管内皮生长因子A（VEGFA）促进眼部疾病中的血管渗漏和水肿。抗VEGFA治疗可能会加重缺氧;因此，需要开发治疗方法。以氧诱导的视网膜病变为模型，检测一氧化氮（NO）在病理性新生血管形成和血管通透性中的作用。在内皮NO合成酶丝氨酸-丙氨酸（S1176 A）突变小鼠中，使用L-NMMA化学或遗传方法实现了NO形成的抑制。抑制NO形成导致视网膜新生血管减少。剩余的血管簇通过稳定的内皮粘附连接表现出减少的血管渗漏，表现为以c-Src依赖的方式减少的血管内皮（VE）-钙粘蛋白Y 685的磷酸化。单剂量L-NMMA治疗视网膜病变可恢复血管屏障并防止渗漏。我们的结论是，NO不稳定的adheren连接，导致血管通透性过高，收敛与VEGFA/VEGFR 2/c-Src/VE-钙粘蛋白途径。这项研究得到了瑞典癌症基金会（19 0119 Pj），瑞典研究理事会（2020-01349），Knut和Alice Wallenberg基金会（KAW 2020.0057）和Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease（17 CVD 03）的支持。KAW还支持LCW与瓦伦堡奖学金（2015.0275）。WCS得到了赠款R35 HL 139945、P01 HL 1070205、AHA MERIT奖的支持。DV得到了德国研究共同体（Deutsche Forschungsgemeinschaft）、SFB 1450、B 03和CRU 342、P2的赠款。
Hypoxia and consequent production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Anti-VEGFA therapeutics may aggravate hypoxia; therefore, therapy development is needed. Oxygen-induced retinopathy was used as a model to test the role of nitric oxide (NO) in pathological neovascularization and vessel permeability. Suppression of NO formation was achieved chemically using L-NMMA, or genetically, in endothelial NO synthase serine to alanine (S1176A) mutant mice. Suppression of NO formation resulted in reduced retinal neoangiogenesis. Remaining vascular tufts exhibited reduced vascular leakage through stabilized endothelial adherens junctions, manifested as reduced phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Treatment with a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage. We conclude that NO destabilizes adheren junctions, resulting in vascular hyperpermeability, by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway. This study was supported by the Swedish Cancer foundation (19 0119 Pj ), the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057) and a Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03). KAW also supported LCW with a Wallenberg Scholar grant (2015.0275). WCS was supported by Grants R35 HL139945, P01 HL1070205, AHA MERIT Award. DV was supported by grants from the Deutsche Forschungsgemeinschaft, SFB1450, B03, and CRU342, P2.