Programming Smooth Muscle Plasticity With Chromatin Dynamics

Abstract

Abstract-Smooth muscle cells (SMCs) possess remarkable phenotypic plasticity that allows rapid adaptation to fluctuating environmental cues. For example, vascular SMCs undergo profound changes in their phenotype during neointimal formation in response to vessel injury or within atherosclerotic plaques. Recent studies have shown that interaction of serum response factor (SRF) and its numerous accessory cofactors with CArG box DNA sequences within promoter chromatin of SMC genes is a nexus for integrating signals that influence SMC differentiation in development and disease. During development, SMC-restricted sets of posttranslational histone modifications are acquired within the CArG box chromatin of SMC genes. These modifications in turn control the chromatin-binding properties of SRF. The histone modifications appear to encode a SMC-specific epigenetic program that is used by extracellular cues to influence SMC differentiation, by regulating binding of SRF and its partners to the chromatin template. Thus, SMC differentiation is dynamically regulated by the interplay between SRF accessory cofactors, the SRF-CArG interaction, and the underlying histone modification program. As such, the inherent plasticity of the SMC lineage offers unique glimpses into how cellular differentiation is dynamically controlled at the level of chromatin within the context of changing microenvironments. Further elucidation of how chromatin regulates SMC differentiation will undoubtedly yield valuable insights into both normal developmental processes and the pathogenesis of several vascular diseases that display detrimental SMC phenotypic behavior. whose expression is restricted to the SMC lineage and required for SMC contraction and regulation of blood pressure under adult physiological conditions. However, unlike skeletal and cardiac myocytes, which are terminally differentiated, SMCs within adult animals readily switch phenotypes in response to changes in local environmental cues. 1 For example, vascular SMCs express high levels of SMC-specific contractile proteins and do not generally proliferate, migrate, or secrete significant amounts of extracellular matrix. However, in response to extracellular cues released at sites of vascular injury or within atherosclerotic lesions, SMCs exhibit decreased expression of SMC-specific contractile proteins and increased migration, proliferation, and production of extracellular matrix components as well as matrix metalloproteases. These changes presumably evolved as an important survival mechanism to repair vascular damage, and the process appears to be fully reversible if the pathological stimuli dissipate. 2 Arteries are especially predisposed to this process, often with fatal consequences resulting from arterioocclusive disease, in which SMC pathophysiology plays a prominent role. Many other parenchymal cell lineages (including endothelial cells, various epithelial cell types, fibroblasts, hepatocytes, chondrocytes, and glial cells) display similar reactive changes in their phenotype under pat...

TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

“…To evaluate potential changes in promoter methylation that may induce gene suppression, further CHIP assays were performed. Tumor necrosis factor-alpha produced H3K27 trimethylation in the histones at the promoter regions of SM-a-actin and SM-MHC at 6 hours after treatment in cultured cerebral vascular SMCs, characteristic of transcriptional suppression 22 ( Figure 7C). Application of TNF-a to rat carotid arteries appeared to produce decreases in H3K4 dimethylation that has also been associated with transcriptional repression 22 ( Figure 7D).…”

“…Tumor necrosis factor-alpha produced H3K27 trimethylation in the histones at the promoter regions of SM-a-actin and SM-MHC at 6 hours after treatment in cultured cerebral vascular SMCs, characteristic of transcriptional suppression 22 ( Figure 7C). Application of TNF-a to rat carotid arteries appeared to produce decreases in H3K4 dimethylation that has also been associated with transcriptional repression 22 ( Figure 7D). In summary, TNF-a appears to recruit histone deacetylase 2 to the promoter region of SMC marker genes producing hypoacetylation and also appears to result in changes in promoter methylation that lead to gene transcriptional repression.…”

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

“…The contractile phenotype of VSMCs is characterized by a low rate of cell proliferation and migration and high expression of contractile proteins such as α‐SMA, SM22 (transgelin), and smooth muscle myosin heavy chain 11 (MYH11) 24, 54, 55, 56, 57. The synthetic phenotype is characterized by a high rate of cell proliferation and migration and decreased expression of contractile proteins 24, 54, 55, 56, 57.…”

“…The contractile phenotype of VSMCs is characterized by a low rate of cell proliferation and migration and high expression of contractile proteins such as α‐SMA, SM22 (transgelin), and smooth muscle myosin heavy chain 11 (MYH11) 24, 54, 55, 56, 57. The synthetic phenotype is characterized by a high rate of cell proliferation and migration and decreased expression of contractile proteins 24, 54, 55, 56, 57. Disruption of the balance of the VSMCs phenotypes (for example, a transition from a contractile phenotype to a synthetic phenotype) will favor VSMCs proliferation and migration, leading to development of neointimal formation and restenosis after vascular injury 24, 55, 56, 57, 58.…”

“…The SRF is a key transcription factor for phenotypic switching of VSMCs by binding to the promoter/regulatory regions of VSMCs‐specific contractile genes, specifically to the cis‐acting DNA sequence CArG box (CC[A/T]6GG), to induce their expression 55, 56, 57, 58. Western blots and real‐time PCR analyses showed that although AGGF1 protein treatment can reverse downregulation of contractile genes/proteins α‐SMA, SM22, and MYH11 by PDGF‐BB in VSMCs, but the effects were completely lost in cells with knockdown of SRF expression by small interfering RNA (+siSRF) (Figure 6G and 6H).…”