Impact of the transcription factor NFAT5 on hypertension-induced arterial remodeling

动脉高血压属于外周动脉疾病、心脏梗死和中风最相关的原因。在这种情况下，动脉平滑肌细胞（VSMC）的长期升高的生物力学应变迫使其表型发生变化，并使动脉血管壁的结构重塑成为可能。在此背景下，我们最近报道了壁应力或生物力学拉伸的增加足以促进活化t细胞核因子5 （NFAT5）的核进入和活化。这种转录因子控制基因产物的表达，如基质分子tenascin-C和细胞骨架蛋白kappa-actin，这两种蛋白都能协调VSMCs的迁移。此外，其活性似乎限制了肺动脉高压的发展和相关的动脉重构过程，相应的小鼠模型证明了这一点，该模型允许诱导smc特异性敲低NFAT5。基于这些发现，我们假设生物力学拉伸的慢性升高刺激vsmc中的NFAT5活性，这是vsmc介导的动脉血管壁重构的先决条件。因此，本研究的重点是了解(i)在拉伸刺激的VSMCs中控制NFAT5活性的机制，以及（ii）其对高血压引起的动脉壁结构变化的功能影响。

Arterial hypertension belongs to the most relevant causes of peripheral artery disease, heart infarction and stroke. Under this condition, the chronically elevated biomechanical strain of arterial smooth muscle cells (VSMC) force a change in their phenotype and enable the structural remodeling of the arterial vessel wall. In this context, we recently reported that an increase in wall stress or biomechanical stretch is sufficient to promote the nuclear entry and activation of nuclear factor of activated T-cells 5 (NFAT5). This transcription factor controls the expression of gene products such as the matrix molecule tenascin-C and the cytoskeletal protein kappa-actin, both of which inter alia orchestrated migration of the VSMCs. Moreover, its activity appeared to be rate-limiting for the development of pulmonary artery hypertension and the associated arterial remodelling process as evidenced by a corresponding mouse model which allows for the inducible SMC-specific knockdown of NFAT5. Based on these findings, we hypothesized that chronic elevation of biomechanical stretch stimulates NFAT5 activity in VSMCs as a prerequisite for the VSMC-mediated remodelling of the arterial vessel wall. Consequently, this proposal is focused on understanding (i) the mechanisms controlling the activity of NFAT5 in stretch-stimulated VSMCs and (ii) its functional influence on hypertension-induced changes in the architecture of the arterial wall.