Endothelial β-arrestins regulate mechanotransduction by the type II bone morphogenetic protein receptor in primary cilia.
Endothelial β-arrestins regulate mechanotransduction by the type II bone morphogenetic protein receptor in primary cilia.
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DOI：
10.1002/pul2.12167
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发表时间：
2022-10
影响因子：
2.6
通讯作者：
Chun, Hyung J.
中科院分区：
文献类型：
--
作者：
Park, Saejeong;Ma, Zhiyuan;Zarkada, Georgia;Papangeli, Irinna;Paluri, Sarin;Nazo, Nour;Rivera-Molina, Felix;Toomre, Derek;Rajagopal, Sudarshan;Chun, Hyung J.
血流动力学对内皮细胞行为和表型的调节涉及许多信号传导成分，包括细胞表面受体、细胞内信号传导中介体、转录因子和表观遗传元件。内皮细胞机械传导的许多信号机制还没有完全确定。在这里，我们试图更好地了解β-抑制蛋白，调节激动剂介导的脱敏和跨膜受体信号整合的细胞内蛋白，如何参与内皮细胞对剪切应力的反应。我们使用β-arrestin敲低的原代内皮细胞进行了体外研究，并使用内皮特异性缺失β-arrestin 1和β-arrestin 2的小鼠进行了体内研究。我们发现β-arrestins定位于内皮细胞的初级纤毛，其存在于相对低剪切状态的内皮细胞亚群中。β-arrestins向纤毛的募集涉及其与纤毛中鞭毛转运蛋白复合物的组分IFFT 81的相互作用。β抑制蛋白敲低导致剪切应力反应显著降低，包括诱导NOS 3表达。在纤毛内，发现β-arrestins与II型骨形态发生蛋白受体（BMPR-II）相关，其破坏类似地导致内皮剪切反应受损。β-arrestins还通过BMPR-II调节Smad转录因子磷酸化。发现内皮特异性缺失β-抑制蛋白1和β-抑制蛋白2的小鼠具有受损的视网膜血管生成。总之，我们已经确定了内皮β-arrestins作为睫状体机械转导的关键转导物的新作用，其在BMPR-II的剪切信号传导中发挥核心作用，并有助于血管发育。
Modulation of endothelial cell behavior and phenotype by hemodynamic forces involves many signaling components, including cell surface receptors, intracellular signaling intermediaries, transcription factors, and epigenetic elements. Many of the signaling mechanisms that underlie mechanotransduction by endothelial cells are inadequately defined. Here we sought to better understand how β‐arrestins, intracellular proteins that regulate agonist‐mediated desensitization and integration of signaling by transmembrane receptors, may be involved in the endothelial cell response to shear stress. We performed both in vitro studies with primary endothelial cells subjected to β‐arrestin knockdown, and in vivo studies using mice with endothelial specific deletion of β‐arrestin 1 and β‐arrestin 2. We found that β‐arrestins are localized to primary cilia in endothelial cells, which are present in subpopulations of endothelial cells in relatively low shear states. Recruitment of β‐arrestins to cilia involved its interaction with IFT81, a component of the flagellar transport protein complex in the cilia. β‐arrestin knockdown led to marked reduction in shear stress response, including induction of NOS3 expression. Within the cilia, β‐arrestins were found to associate with the type II bone morphogenetic protein receptor (BMPR‐II), whose disruption similarly led to an impaired endothelial shear response. β‐arrestins also regulated Smad transcription factor phosphorylation by BMPR‐II. Mice with endothelial specific deletion of β‐arrestin 1 and β‐arrestin 2 were found to have impaired retinal angiogenesis. In conclusion, we have identified a novel role for endothelial β‐arrestins as key transducers of ciliary mechanotransduction that play a central role in shear signaling by BMPR‐II and contribute to vascular development.
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DOI：
10.1074/jbc.m116.754887
发表时间：
2016-12-30
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Alvarez-Curto E;Inoue A;Jenkins L;Raihan SZ;Prihandoko R;Tobin AB;Milligan G
通讯作者：
Milligan G
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT
影响因子：
4.8
作者：
Boo, YC;Sorescu, G;Jo, HJ
通讯作者：
Jo, HJ
影响因子：
9.8
作者：
Maleszewska M;Vanchin B;Harmsen MC;Krenning G
通讯作者：
Krenning G
影响因子：
7.7
作者：
Dinsmore, Colin;Reiter, Jeremy F.
通讯作者：
Reiter, Jeremy F.