Notch signaling regulates arterial vasoreactivity through opposing functions of Jagged1 and Dll4 in the vessel wall
Notch signaling regulates arterial vasoreactivity through opposing functions of Jagged1 and Dll4 in the vessel wall
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DOI：
10.1152/ajpheart.00293.2018
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发表时间：
2018-12-01
影响因子：
4.8
通讯作者：
Proweller, Aaron
中科院分区：
文献类型：
--
作者：
Basu, Sanchita;Barbur, Iulia;Proweller, Aaron
动脉壁中内皮细胞（EC）和平滑肌细胞（SMC）之间的功能相互作用对于控制血管反应性是必要的，而血管反应性是血管阻力和张力的基础。肌球蛋白轻链激酶（MLCK）和肌球蛋白磷酸酶（MP）的相对活性相互协调，使肌球蛋白轻链（p-MLC）的磷酸化成为平滑肌细胞产生力的分子标志。血管壁中的Notch信号传导在动脉形成和成熟中起关键作用，并且已经涉及动脉血管调节。在这份报告中，我们假设Notch信号通过配体Jagged 1（在SMC中）和δ样蛋白-4（Dll 4;在EC中）通过同型（SMC-SMC）和异型（EC-SMC）细胞相互作用调节血管反应性。使用配体诱导测定，我们证明Jagged 1选择性地诱导平滑肌MLCK基因表达和p-MLC含量，同时抑制MP功能（即，增加的Ca 2+敏化）。同样，选择性缺乏小鼠平滑肌Jagged 1导致MLCK和p-MLC丢失，降低Ca（2+）敏感性。以及通过肌描记术测量的受损的动脉力产生。相比之下，由Dll 4触发的平滑肌Notch信号增加了MP靶向亚基1（MYPT 1; MP调节亚基）的表达，而来自内皮Dll 4缺陷小鼠的动脉的特征是MYPT 1水平降低，力产生增强，以及不依赖于内皮源性一氧化氮信号的松弛受损。加在一起。本研究鉴定了血管壁中配体特异性Notch信号传导的新的相反血管调节功能，强调了EC和SMC之间的指令性信号传导，并表明Notch信号在动脉张力控制中可能表现为“变阻器”。平滑肌锯齿蛋白1和内皮细胞δ样蛋白-4配体分别表现出对肌球蛋白轻链激酶和肌球蛋白磷酸酶靶向亚基1/肌球蛋白磷酸酶的选择性调节，提供了Notch信号调节血管平滑肌收缩活性的机制联系。这些发现可能为Notch信号传导缺陷的人类综合征中观察到的血管紊乱提供信息，同时为动脉生理功能提供基本的分子见解。
Functional interactions between endothelial cells (ECs) and smooth muscle cells (SMCs) in the arterial wall are necessary for controlling vasoreactivity that underlies vascular resistance and tone. Key signaling pathways converge on the phosphorylation of myosin light chain (p-MLC), the molecular signature of force production in SMCs, through coordinating the relative activities of myosin light chain kinase (MLCK) and myosin phosphatase (MP). Notch signaling in the vessel wall serves critical roles in arterial formation and maturation and has been implicated in arterial vasoregulation. In this report, we hypothesized that Notch signaling through ligands Jagged1 (in SMCs) and delta-like protein-4 (Dll4; in ECs) regulates vasoreactivity via homotypic (SMC-SMC) and heterotypic (EC-SMC) cell interactions. Using ligand induction assays, we demonstrated that Jagged1 selectively induced smooth muscle MLCK gene expression and p-MLC content while inhibiting MP function (i.e., increased Ca2+ sensitization) in a Rho kinase II-dependent manner. Likewise, selective deficiency of smooth muscle Jagged1 in mice resulted in MLCK and p-MLC loss, reduced Ca(2+)sensitization. and impaired arterial force generation measured by myography. In contrast, smooth muscle Notch signaling triggered by Dll4 increased expression of MP-targeting subunit 1 (MYPT1; the MP regulatory subunit), whereas arteries from endothelial Dll4-deficient mice featured reduced MYPT1 levels, enhanced force production, and impaired relaxation independent of endothelium-derived nitric oxide signaling. Taken together. this study identifies novel opposing vasoregulatory functions for ligand-specific Notch signaling in the vessel wall, underscoring instructional signaling between ECs and SMCs and suggesting that Notch signals might behave as a "rheostat" in arterial tone control.NEW & NOTEWORTHY The present study unveils novel roles for ligand-specific Notch signaling in arterial function. Smooth muscle Jaggedl and endothelial cell delta-like protein-4 ligands exhibit selective regulation of myosin light chain kinase and myosin phosphatase-targeting subunit 1/myosin phosphatase, respectively, providing a mechanistic link through which Notch signals modulate contractile activities in vascular smooth muscle. These findings may inform vascular derangements observed in human syndromes of Notch signaling deficiency while offering fundamental molecular insights into arterial physiological function.