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

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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.