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An autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through deregulated VEGFA, NOS1, and CTNNB1
Autophagy ( IF 13.3 ) Pub Date : 2020-06-17 , DOI: 10.1080/15548627.2020.1778292
Bora Lee 1 , Hyejin Shin 1 , Ji-Eun Oh 2 , Jaekyoung Park 1 , Mira Park 3 , Seung Chel Yang 3 , Jin-Hyun Jun 4, 5 , Seok-Ho Hong 6 , Haengseok Song 3 , Hyunjung Jade Lim 1, 2
Affiliation  

ABSTRACT

The uterus undergoes vascular changes during the reproductive cycle and pregnancy. Steroid hormone deprivation induces macroautophagy/autophagy in major uterine cell types. Herein, we explored the functions of uterine autophagy using the Amhr2-Cre-driven atg7 deletion model. Deletion of Atg7 was confirmed by functional deficit of autophagy in uterine stromal, myometrial, and vascular smooth muscle cells, but not in endothelial cells. atg7d/d uteri exhibited enhanced stromal edema accompanied by dilation of blood vessels. Ovariectomized atg7d/d uteri showed decreased expression of endothelial junction-related proteins, such as CTNNB1/beta-catenin, with increased vascular permeability, and increased expression of VEGFA and NOS1. Nitric oxide (NO) was shown to mediate VEGFA-induced vascular permeability by targeting CTNNB1. NO involvement in maintaining endothelial junctional stability in atg7d/d uteri was confirmed by the reduction in extravasation following treatment with a NOS inhibitor. We also showed that atg7d/d uterine phenotype improved the fetal weight:placental weight ratio, which is one of the indicators of assessing the status of preeclampsia. We showed that autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through the deregulation of VEGFA, NOS1, and CTNNB1.

Abbreviations: ACTA2: actin, alpha 2, smooth muscle, aortic; Amhr2: anti-Mullerian hormone type 2 receptor; ANGPT1: angiopoietin 1; ATG: autophagy-related; CDH5: cadherin 5; CLDN5: claudin 5; COL1A1: collagen, type I, alpha 1; CSPG4/NG2: chondroitin sulfate proteoglycan 4; CTNNB1: catenin (cadherin associated protein), beta 1; DES: desmin; EDN1: endothelin 1; EDNRB: endothelin receptor type B; F3: coagulation factor III; KDR/FLK1/VEGFR2: kinase insert domain protein receptor; LYVE1: lymphatic vessel endothelial hyaluronan receptor 1; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MCAM/CD146: melanoma cell adhesion molecule; MYL2: myosin, light polypeptide 2, regulatory, cardiac, slow; MYLK: myosin, light polypeptide kinase; NOS1/nNOS: nitric oxide synthase 1, neuronal; NOS2/iNOS: nitric oxide synthase 2, inducible; NOS3/eNOS: nitric oxide synthase 3, endothelial cell; OVX: ovariectomy; PECAM1/CD31: platelet/endothelial cell adhesion molecule 1; POSTN: periostin, osteoblast specific factor; SQSTM1: sequestosome 1; TEK/Tie2: TEK receptor tyrosine kinase; TJP1/ZO-1: tight junction protein 1; TUBB1, tubulin, beta 1 class VI; USC: uterine stromal cell; VEGFA: vascular endothelial growth factor A; VSMC: vascular smooth muscle cell.



中文翻译:

子宫血管微环境中的自噬缺陷通过失调的 VEGFA、NOS1 和 CTNNB1 引起高渗透性

摘要

子宫在生殖周期和怀孕期间会发生血管变化。类固醇激素剥夺诱导主要子宫细胞类型中的巨自噬/自噬。在此,我们使用Amhr2-Cre驱动的atg7缺失模型探索了子宫自噬的功能。Atg7的缺失通过子宫间质、肌层和血管平滑肌细胞中自噬的功能缺陷得到证实,但在内皮细胞中则不然。atg7 d/d子宫表现出增强的基质水肿并伴有血管扩张。卵巢切除atg7 d/d子宫内皮连接相关蛋白(如 CTNNB1/β-连环蛋白)的表达降低,血管通透性增加,VEGFA 和 NOS1 的表达增加。一氧化氮 (NO) 显示通过靶向 CTNNB1 介导 VEGFA 诱导的血管通透性。用 NOS 抑制剂治疗后外渗减少证实了在atg7 d/d子宫内维持内皮连接稳定性的过程中没有参与。我们还证明了atg7 d/d子宫表型改善了胎儿体重:胎盘重量比,这是评估先兆子痫状态的指标之一。我们发现子宫血管微环境中的自噬缺陷通过 VEGFA、NOS1 和 CTNNB1 的失调引起高渗透性。

缩写: ACTA2:肌动蛋白、α2、平滑肌、主动脉;Amhr2:抗苗勒管激素 2 型受体;ANGPT1:血管生成素 1;ATG:自噬相关;CDH5:钙粘蛋白 5;CLDN5:密蛋白 5;COL1A1:胶原蛋白,I 型,α 1;CSPG4/NG2:硫酸软骨素蛋白聚糖4;CTNNB1:连环蛋白(钙粘蛋白相关蛋白),β1;DES:结蛋白;EDN1:内皮素 1;EDNRB:B型内皮素受体;F3:凝血因子III;KDR/FLK1/VEGFR2:激酶插入域蛋白受体;LYVE1:淋巴管内皮透明质酸受体1;MAP1LC3B:微管相关蛋白 1 轻链 3 β;MCAM/CD146:黑色素瘤细胞粘附分子;MYL2:肌球蛋白,轻多肽 2,调节,强心,慢;MYLK:肌球蛋白,轻多肽激酶;NOS1/nNOS:一氧化氮合酶 1,神经元;NOS2/iNOS:一氧化氮合酶 2,诱导型;NOS3/eNOS:一氧化氮合酶 3,内皮细胞;OVX:卵巢切除术;PECAM1/CD31:血小板/内皮细胞粘附分子1;POSTN:骨膜素,成骨细胞特异性因子;SQSTM1:隔离体 1;TEK/Tie2:TEK 受体酪氨酸激酶;TJP1/ZO-1:紧密连接蛋白 1;TUBB1,微管蛋白,beta 1 VI 类;USC:子宫基质细胞;VEGFA:血管内皮生长因子A;VSMC:血管平滑肌细胞。

更新日期:2020-06-17
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