University Bordeaux, INSERM, Biologie des maladies cardiovasculaires, Pessac, France (P.B., M.L.B., V.D., S.R., J.V., T.C., C.D., P.D.).
CHU de Bordeaux, Service de Biochimie clinique, France (M.L.B.).
Arterioscler Thromb Vasc Biol. 2023 Jul;43(7):1199-1218. doi: 10.1161/ATVBAHA.123.319106. Epub 2023 May 18.
Endothelial cells (ECs) are sensitive to physical forces created by blood flow, especially to laminar shear stress. Among the cell responses to laminar flow, EC polarization against the flow direction emerges as a key event, particularly during the development and remodeling of the vascular network. EC adopt an elongated planar cell shape with an asymmetrical distribution of intracellular organelles along the axis of blood flow. This study aimed to investigate the involvement of planar cell polarity via the receptor ROR2 (receptor tyrosine kinase-like orphan receptor 2) in endothelial responses to laminar shear stress.
We generated a genetic mouse model with EC-specific deletion of , in combination with in vitro approaches involving loss- and gain-of-function experiments.
During the first 2 weeks of life, the endothelium of the mouse aorta undergoes a rapid remodeling associated with a loss of EC polarization against the flow direction. Notably, we found a correlation between ROR2 expression and endothelial polarization levels. Our findings demonstrate that deletion of in murine ECs impaired their polarization during the postnatal development of the aorta. In vitro experiments further validated the essential role of ROR2 in both EC collective polarization and directed migration under laminar flow conditions. Exposure to laminar shear stress triggered the relocalization of ROR2 to cell-cell junctions where it formed a complex with VE-Cadherin and β-catenin, thereby regulating adherens junctions remodeling at the rear and front poles of ECs. Finally, we showed that adherens junctions remodeling and cell polarity induced by ROR2 were dependent on the activation of the small GTPase Cdc42.
This study identified ROR2/planar cell polarity pathway as a new mechanism controlling and coordinating collective polarity patterns of EC during shear stress response.
内皮细胞（ECs）对外界血流产生的力十分敏感，尤其是层流剪切力。在细胞对层流的反应中，EC 沿血流方向的极化是一个关键事件，特别是在血管网络的发育和重塑过程中。EC 呈现出一种狭长的平面细胞形态，细胞内细胞器沿着血流轴呈不对称分布。本研究旨在通过受体 ROR2（受体酪氨酸激酶样孤儿受体 2）探讨平面细胞极性在 EC 对层流剪切力反应中的作用。
我们构建了内皮细胞特异性敲除 的基因敲除小鼠模型，同时进行了体外的失活和激活实验。
在出生后前 2 周，小鼠主动脉的内皮经历了一个快速的重塑过程，伴随有 EC 沿血流方向极化的丧失。值得注意的是，我们发现 ROR2 的表达与内皮极化水平之间存在相关性。我们的研究结果表明，在主动脉的出生后发育过程中，内皮细胞特异性敲除 会损害其极化。体外实验进一步验证了 ROR2 在 EC 集体极化和在层流条件下定向迁移中的关键作用。层流剪切力刺激 ROR2 重新定位到细胞-细胞连接处，在该处与 VE-钙黏蛋白和β-连环蛋白形成复合物，从而调节 EC 后极和前极的黏附连接重塑。最后，我们表明 ROR2 诱导的黏附连接重塑和细胞极性依赖于小 GTPase Cdc42 的激活。
本研究确定了 ROR2/平面细胞极性途径作为一种新的机制，控制和协调了 EC 在剪切力反应过程中的集体极性模式。
