Mechanotransduction Induced Interplay between Phospholamban and Yes Activated Protein Induces Smooth Muscle Cell Hypertrophy.

The gastrointestinal system is a hollow organ affected by fibrostenotic diseases that cause volumetric compromise of the lumen via smooth muscle hypertrophy and fibrosis. Many of the driving mechanisms remain unclear. Yes-associated protein-1 (YAP) is a critical mechanosensory transcriptional regulator that mediates cell hypertrophy in response to elevated extracellular rigidity. In the type 2 inflammatory disorder, eosinophilic esophagitis (EoE), phospholamban (PLN) can induce smooth muscle cell hypertrophy. We used EoE as a disease model for understanding a mechanistic pathway in which PLN and YAP interact in response to rigid extracellular substrate to induce smooth muscle cell hypertrophy. PLN induced YAP nuclear sequestration in a feed forward loop that caused increased cell size in response to rigid substrate. This mechanism of rigidity sensing may have previously unappreciated clinical implications for PLN expressing hollow systems such as the esophagus and heart.