Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, USA.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Cell Rep. 2019 Aug 27;28(9):2397-2412.e4. doi: 10.1016/j.celrep.2019.07.072.
The lymphatic vasculature requires intraluminal valves to maintain forward lymph flow. Lymphatic valves form and are constantly maintained by oscillatory fluid flow throughout life, yet the earliest steps of how lymphatic endothelial cells are able to respond to fluid shear stress remain unknown. Here, we show that the adherens junction protein VE-cadherin is required for the upregulation of valve-specific transcription factors. Conditional deletion of VE-cadherin in vivo prevented valve formation in the embryo and caused postnatal regression of nearly all lymphatic valves in multiple tissues. Since VE-cadherin is known to signal through β-catenin and the VEGFR/AKT pathway, each pathway was probed. Expression of a constitutively active β-catenin mutant or direct pharmacologic activation of AKT in vivo significantly rescued valve regression in the VE-cadherin-deficient lymphatic vessels. In conclusion, VE-cadherin-dependent signaling is required for lymphatic valve formation and maintenance and therapies to augment downstream pathways hold potential to treat lymphedema in patients.
淋巴脉管系统需要管腔内瓣膜来维持淋巴向前流动。淋巴瓣膜在一生中通过振荡液流形成并不断维持，但淋巴内皮细胞如何能够响应流体切应力的最早步骤仍然未知。在这里，我们表明黏着连接蛋白 VE-cadherin 是上调瓣膜特异性转录因子所必需的。体内条件性敲除 VE-cadherin 可防止胚胎中的瓣膜形成，并导致出生后多种组织中几乎所有的淋巴瓣膜退化。由于 VE-cadherin 已知通过 β-catenin 和 VEGFR/AKT 途径发出信号，因此每条途径都进行了探测。体内表达组成型活性 β-catenin 突变体或直接药理学激活 AKT 可显著挽救 VE-cadherin 缺陷性淋巴管中的瓣膜退化。总之，VE-cadherin 依赖性信号传导对于淋巴瓣膜的形成和维持是必需的，并且增强下游途径的疗法有可能治疗患者的淋巴水肿。
