当前位置: X-MOL 学术Circ. Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
VE-Cadherin Is Required for Cardiac Lymphatic Maintenance and Signaling
Circulation Research ( IF 16.5 ) Pub Date : 2021-11-18 , DOI: 10.1161/circresaha.121.318852
Natalie R Harris 1 , Natalie R Nielsen 1 , John B Pawlak 1 , Amir Aghajanian 2 , Krsna Rangarajan 1 , D Stephen Serafin 1 , Gregory Farber 3, 4 , Danielle M Dy 1 , Nathan P Nelson-Maney 1 , Wenjing Xu 1 , Disha Ratra 1 , Sophia H Hurr 1 , Li Qian 3 , Joshua P Scallan 5 , Kathleen M Caron 1
Affiliation  

Background:The adherens protein VE-cadherin (vascular endothelial cadherin) has diverse roles in organ-specific lymphatic vessels. However, its physiological role in cardiac lymphatics and its interaction with lymphangiogenic factors has not been fully explored. We sought to determine the spatiotemporal functions of VE-cadherin in cardiac lymphatics and mechanistically elucidate how VE-cadherin loss influences prolymphangiogenic signaling pathways, such as adrenomedullin and VEGF (vascular endothelial growth factor)-C/VEGFR3 (vascular endothelial growth factor receptor 3) signaling.Methods:Cdh5flox/flox;Prox1CreERT2 mice were used to delete VE-cadherin in lymphatic endothelial cells across life stages, including embryonic, postnatal, and adult. Lymphatic architecture and function was characterized using immunostaining and functional lymphangiography. To evaluate the impact of temporal and functional regression of cardiac lymphatics in Cdh5flox/flox;Prox1CreERT2 mice, left anterior descending artery ligation was performed and cardiac function and repair after myocardial infarction was evaluated by echocardiography and histology. Cellular effects of VE-cadherin deletion on lymphatic signaling pathways were assessed by knockdown of VE-cadherin in cultured lymphatic endothelial cells.Results:Embryonic deletion of VE-cadherin produced edematous embryos with dilated cardiac lymphatics with significantly altered vessel tip morphology. Postnatal deletion of VE-cadherin caused complete disassembly of cardiac lymphatics. Adult deletion caused a temporal regression of the quiescent epicardial lymphatic network which correlated with significant dermal and cardiac lymphatic dysfunction, as measured by fluorescent and quantum dot lymphangiography, respectively. Surprisingly, despite regression of cardiac lymphatics, Cdh5flox/flox;Prox1CreERT2 mice exhibited preserved cardiac function, both at baseline and following myocardial infarction, compared with control mice. Mechanistically, loss of VE-cadherin leads to aberrant cellular internalization of VEGFR3, precluding the ability of VEGFR3 to be either canonically activated by VEGF-C or noncanonically transactivated by adrenomedullin signaling, impairing downstream processes such as cellular proliferation.Conclusions:VE-cadherin is an essential scaffolding protein to maintain prolymphangiogenic signaling nodes at the plasma membrane, which are required for the development and adult maintenance of cardiac lymphatics, but not for cardiac function basally or after injury.

中文翻译:

VE-钙粘蛋白是心脏淋巴维持和信号传导所必需的

背景:粘附蛋白 VE-钙粘蛋白(血管内皮钙粘蛋白)在器官特异性淋巴管中具有多种作用。然而,其在心脏淋巴管中的生理作用及其与淋巴管生成因子的相互作用尚未得到充分探索。我们试图确定 VE-钙粘蛋白在心脏淋巴管中的时空功能,并从机制上阐明 VE-钙粘蛋白丢失如何影响促淋巴管生成信号通路,例如肾上腺髓质素和 VEGF(血管内皮生长因子)-C/VEGFR3(血管内皮生长因子受体 3) signaling.Methods: Cdh5 flox/flox ;Prox1CreER T2小鼠被用来删除整个生命阶段(包括胚胎、出生后和成人)淋巴管内皮细胞中的 VE-钙粘蛋白。使用免疫染色和功能性淋巴管造影术表征淋巴结构和功能。评估Cdh5 flox/flox中心脏淋巴管时间和功能消退的影响;Prox1CreER T2小鼠,结扎左前降支动脉,并通过超声心动图和组织学评估心肌梗死后的心脏功能和修复。通过敲低培养的淋巴管内皮细胞中的 VE-钙粘蛋白,评估 VE-钙粘蛋白缺失对淋巴信号通路的细胞影响。结果:VE-钙粘蛋白的胚胎缺失产生水肿胚胎,心脏淋巴管扩张,血管尖端形态显着改变。VE-钙粘蛋白的出生后缺失导致心脏淋巴管完全分解。成人缺失导致静止的心外膜淋巴网络暂时退化,这与显着的皮肤和心脏淋巴功能障碍相关,分别通过荧光和量子点淋巴管造影术测量。令人惊讶的是,尽管心脏淋巴管退化了,Cdh5 flox/flox;与对照小鼠相比,Prox1CreER T2小鼠在基线和心肌梗塞后均表现出保留的心脏功能。从机制上讲,VE-钙粘蛋白的缺失会导致 VEGFR3 的异常细胞内化,从而排除 VEGFR3 被 VEGF-C 规范激活或被肾上腺髓质素信号转导非规范反式激活的能力,从而损害细胞增殖等下游过程。结论:VE-钙粘蛋白是一种重要的支架蛋白,用于维持质膜上的促淋巴管生成信号节点,这是心脏淋巴管发育和成人维持所必需的,但对于基础或损伤后的心脏功能则不需要。
更新日期:2022-01-08
down
wechat
bug