Mechanosensitive transcriptional regulation of gene expression in smooth muscle. Implications for health and disease

Abstract: Smooth muscle participates in forming the wall of hollow organs, tracts, and blood vessels. Therefore, it plays a critical role in mediating vital functions in the body including regulation of blood pressure. In response to changes in the surrounding microenvironment, smooth muscle cells can modulate their phenotype and dedifferentiate from being quiescent contractile to a more proliferative and migratory phenotype. The mechanical force represents aprinciple part of the microenvironment cues. Smooth muscle senses the mechanical force and converts it into a biochemical signal that affects gene expression eventually. Until now, there are two known families of mechanosensitive transcriptional regulators; myocardin-related transcription factors (MRTFs); and the downstream effectors of the Hippo signaling pathway, Yes-associated proteins (YAP), and closely related transcriptional coactivator with PDZ-binding motif (TAZ). However, the role of these mechanosensitive transcriptional regulators and their contribution to smooth muscle homeostasis and disease are not well understood.This work demonstrated the lethal impact of inducible deletion of YAP/TAZ in adult smooth muscle and showed that YAP and TAZ are critical for short- and long-term mechanotransduction. Arteries that lack YAP/TAZ have impaired agonist- and pressure-induced contraction which resulted in multiple vascular lesions under hypertensive setting. These findings suggest a protective role of YAP/TAZ against arterial damage caused by hypertension which is well-known risk factor for cardiovascular diseases. In addition to hypertension, atherosclerosis is also considered a risk factor for cardiovascular diseases. We investigated the role of MRTFA in foam cell formation which is a hallmark of atherosclerosis. We found that MRTFA stimulates lipid accumulation in human vascular cells by multiple mechanisms including, increased pinocytosis, decreased lipid efflux, and upregulation of LDL receptor. These changes collectively participate in converting smooth muscle cells into foam cells. We alsoexamined the relationship between MRTFA and unfolded protein response. We noticed tight negative correlation between smooth muscle markers and unfolded protein response in three well-recognized examples of phenotypic modulation in vivo. We also induced the unfolded protein response chemically in vitro and we observed that MRTFA could ameliorate the induction of unfolded protein response.In summary, these results demonstrated essential roles of YAP/TAZ and MRTFA for smooth muscle structure and function, providing new insights into their physiological functions, as well as their role in disease development andprogression, in particular the vascular diseases. However, further studies are needed to propose new potential therapeutic targets against diseases with underlying smooth muscle modulation.