Department of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.
Division of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany.
FASEB J. 2019 Mar;33(3):3364-3377. doi: 10.1096/fj.201801594R. Epub 2018 Nov 1.
The arterial wall adapts to alterations in blood flow and pressure by remodeling the cellular and extracellular architecture. Biomechanical stress of vascular smooth muscle cells (VSMCs) in the media is thought to precede this process and promote their activation and subsequent proliferation. However, molecular determinants orchestrating the transcriptional phenotype under these conditions have been insufficiently studied. We identified the transcription factor, nuclear factor of activated T cells 5 (NFAT5; or tonicity enhancer-binding protein) as a crucial regulatory element of mechanical stress responses of VSMCs. Here, the relevance of NFAT5 for arterial growth and thickening is investigated in mice upon inducible smooth muscle cell (SMC)-specific genetic ablation of Nfat5. In cultured mouse VSMCs, loss of Nfat5 inhibits the expression of gene sets involved in the control of the cell cycle and the interaction with the extracellular matrix and cytoskeletal dynamics. In vivo, SMC-specific knockout of Nfat5 did not affect the general vascular architecture and blood pressure levels under baseline conditions. However, proliferation of VSMCs and the thickening of the arterial wall were inhibited during both flow-induced collateral remodeling and hypertension-mediated arterial hypertrophy. Whereas originally described as a hypertonicity-responsive transcription factor, these findings identify NFAT5 as a novel molecular determinant of biomechanically induced phenotype changes of VSMCs and wall stress-induced arterial remodeling processes.-Arnold, C., Feldner, A., Zappe, M., Komljenovic, D., De La Torre, C., Ruzicka, P., Hecker, M., Neuhofer, W., Korff, T. Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice.
动脉壁通过重塑细胞和细胞外结构来适应血流和压力的变化。人们认为，中膜血管平滑肌细胞（VSMCs）的生物力学应激先于这个过程，并促进其激活和随后的增殖。然而，在这些条件下协调转录表型的分子决定因素尚未得到充分研究。我们确定了转录因子激活 T 细胞核因子 5（NFAT5；或张力增强结合蛋白）作为 VSMC 机械应激反应的关键调节元件。在这里，研究了在可诱导的平滑肌细胞（SMC）特异性 NFAT5 基因缺失的小鼠中，NFAT5 对动脉生长和增厚的相关性。在培养的小鼠 VSMCs 中，NFAT5 的缺失抑制了参与细胞周期控制以及与细胞外基质和细胞骨架动力学相互作用的基因集的表达。在体内，SMC 特异性敲除 Nfat5 不会影响基础条件下的一般血管结构和血压水平。然而，在血流诱导的侧支重塑和高血压介导的动脉肥大过程中，VSMC 的增殖和动脉壁的增厚受到抑制。虽然最初被描述为高渗性反应转录因子，但这些发现确定 NFAT5 是 VSMC 生物力学诱导表型变化和壁应力诱导动脉重塑过程的新型分子决定因素。-阿诺德，C.，费尔德纳，A.，扎普，M.，科姆列诺维奇，D.，德拉托雷，C.，鲁齐卡，P.，海克，M.，诺伊霍弗，W.，科尔夫，T. NFAT5/TonEBP 在平滑肌细胞中的基因缺失会损害小鼠的血流和压力诱导的动脉重塑。
