Forgetting to Switch Off SMAD2 in Aneurysmal Disease
Vascular smooth muscle cells (VSMCs) are key component cells of the vascular wall that are critical for contractility of the aorta.1 They respond to biochemical and mechanical signals and play an important role in the regulation of blood pressure. Dysregulation of VSMCs is a hallmark of cardiovascular diseases such as restenosis, hypertension, aneurysms, and atherosclerosis. Investigating the signaling pathways in both normal and dysregulated VSMCs is important for understanding how these cardiovascular diseases develop and for the development of more effective therapies for these potentially life-threatening disorders.
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Aneurysms are dangerous vascular diseases characterized by aortic dilatation with thinning of the medial VSMC layer. Several mechanisms have been implicated in the development of human aortic aneurysms, including the role of transforming growth factor-β1 (TGF-β1), although there are some controversies in the field.2–6 Evidence shows that VSMCs from thoracic aortic aneurysms (TAA) exhibit enhanced activity of SMAD2, a transcription factor that is part of the canonical TGF-β1 pathway and a key effector of the actions of TGF-β1.7 TGF-β1 signaling results in the phosphorylation and translocation of cytoplasmic SMAD2 into the nucleus and consequent transcriptional activation of its target genes.8,9 However, the activation of SMAD2 in TAA has previously been shown to be dissociated from the TGF-β1 pathway. Instead, the SMAD2 hyperactivity is suggested to be attributed to the constitutive overexpression of SMAD2 at the transcriptional level.10 Furthermore, SMAD2 overexpression was associated with key chromatin histone modifications at the SMAD2 promoter, suggesting an element of epigenetic control.10
In the nucleus of mammalian cells, chromosomal DNA is tightly packaged into chromatin, a higher-order structure comprised of subunits called nucleosomes. Each nucleosome consists of an …