Vascular Control of Organ Function
Impact of vascular NFAT5 on lung function and responses to hypoxia
Alveolar gas exchange in the lung is maintained by matching ventilation and perfusion through mechanisms reversibly restricting blood perfusion of less ventilated (hypoxic) areas. However, chronic hypoxia as it develops due to e.g. chronic obstructive pulmonary diseases, decreased ventilatory drive or intraalveolar exudates contributes to both inflammation and irreversible structural remodeling of the lung. As a consequence, the resistance of pulmonary arteries increases which may impair lung perfusion as well as blood oxygenation and eventually lead to right heart hypertrophy and congestive hepatopathy. Although vascular cells have been reported to control crucial short- and long-term responses of the hypoxic lung, molecular determinants regulating the corresponding context-specific adaptations of their transcriptome as well as their influence on tissue-specific (dys)functions are largely unknown.
We observed that nuclear factor of activated T-cells 5 (NFAT5 or tonicity enhancer binding protein, TonEBP) is expressed in vascular endothelial and smooth muscle cells of the hypoxic lung and seek to expore its role in regulating hypoxia-induced pulmonary muscularization, activation of alveolar macrophages and vascular integrity. Based on the use of mouse models allowing for the conditional endothelial and smooth muscle cell-specific genetic ablation of NFAT5, we intend to delineate the NFAT5-dependent modification of the vascular transcriptome and its impact on hypoxic stress-mediated cellular crosstalk in the lung that controls tissue-specific responses.