Vascular smooth muscle cell phenotype is defined by Ca2+-dependent transcription factors

Abstract

Ca(2+) is an important second messenger in vascular smooth muscle cells (VSMCs). Therefore, VSMCs exercise tight control of the intracellular Ca(2+) concentration ([Ca(2+)]i) by expressing a wide repertoire of Ca(2+) channels and transporters. The presence of several pathways for Ca(2+) influx and efflux provides many possibilities for controlling [Ca(2+)]i in a spatial and temporal manner. Intracellular Ca(2+) has a dual role in VSMCs; first, it is necessary for VSMC contraction; and, second, it can activate multiple transcription factors. These factors are cAMP response element-binding protein, nuclear factor of activated T lymphocytes, and serum response factor. Furthermore, it was recently reported that the C-terminus of voltage-dependent L-type Ca(2+) calcium channels can regulate transcription in VSMCs. Transcription regulation in VSMCs modulates the expression patterns of genes, including genes coding for contractile and cytoskeleton proteins, and those promoting proliferation and cell growth. Depending on their gene expression, VSMCs can exist in different functional states or phenotypes. The majority of healthy VSMCs show a contractile phenotype, characterized by high contractile ability and a low proliferative rate. However, VSMCs can undergo phenotypic modulation with different physiological and pathological stimuli, whereby they start to proliferate, migrate, and synthesize excessive extracellular matrix. These events are associated with injury repair and angiogenesis, but also with the development of cardiovascular pathologies, such as atherosclerosis and hypertension. This review discusses the currently known Ca(2+)-dependent transcription factors in VSMCs, their regulation by Ca(2+) signalling, and their role in the VSMC phenotype.

Keywords: CREB; calcium (Ca2+) signalling; nuclear factor of activated T lymphocytes (NFAT); transcription; vascular smooth muscle cell phenotype.