MicroRNA Regulation in Smooth Muscle Cell Differentiation

Smooth muscle cells (SMCs) exhibit remarkable plasticity, transitioning between a quiescent, contractile phenotype and a synthetic, proliferative state in response to developmental cues, vascular injury or pathological stimuli. Core transcriptional regulators such as serum response factor, myocardin and Krüppel-like factor-4 (KLF4) govern the expression of contractile genes, including α-smooth muscle actin (αSMA), calponin and SM22α. MicroRNAs (miRNAs), a class of ∼22-nucleotide non-coding RNAs, fine-tune this regulatory network by post-transcriptionally repressing key targets. Among these, the miR-143/145 cluster is indispensable for promoting the contractile programme by suppressing factors that inhibit differentiation, such as KLF4 and ELK1. Other miRNAs, including miR-21, miR-29 and miR-125b, modulate extracellular matrix deposition, growth factor signalling and cytoskeletal organisation, thereby influencing SMC phenotype and vessel wall integrity. Dysregulation of miRNA networks contributes to vascular disorders—atherosclerosis, restenosis and hypertension—by tipping the balance towards pathological SMC activation. Understanding miRNA-mediated circuits has also opened new avenues in vascular tissue engineering and regenerative medicine, where manipulation of specific miRNAs can enhance the maturity and function of engineered constructs or stem cell-derived SMCs.

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MicroRNA Regulation in Smooth Muscle Cell Differentiation publication trend

The graph below shows the total number of articles in microrna regulation in smooth muscle cell differentiation across all publications each year (not limited to Nature Index journals).

Technical terms

microRNA (miRNA): A small, non-coding RNA molecule that binds to complementary messenger RNA sequences to repress translation or induce degradation.

Smooth muscle cell (SMC) differentiation: The process by which precursor or synthetic SMCs acquire a quiescent, contractile phenotype characterised by expression of specific cytoskeletal and contractile proteins.

Phenotypic switch: The reversible transition of SMCs between a contractile state and a synthetic state, affecting proliferation, migration and extracellular matrix synthesis.

Kruppel-like factor-4 (KLF4): A transcription factor that antagonises the contractile gene programme and whose downregulation by miRNAs promotes SMC differentiation.

α-Smooth muscle actin (αSMA): A cytoskeletal protein and hallmark marker of differentiated, contractile smooth muscle cells.

References

1. A seed sequence variant in miR-145-5p causes multisystem smooth muscle dysfunction syndrome. Journal of Clinical Investigation (2023).
2. Defining the Role of the miR-145—KLF4—αSMA Axis in Mitral Valvular Interstitial Cell Activation in Myxomatous Mitral Valve Prolapse Using the Canine Model. International Journal of Molecular Sciences (2024).
3. MicroRNAs in vascular tissue engineering and post-ischemic neovascularization. Advanced Drug Delivery Reviews (2015).
4. The function of miR-143, miR-145 and the MiR-143 host gene in cardiovascular development and disease. Vascular Pharmacology (2018).
5. MicroRNA‐125b in vascular diseases: An updated systematic review of pathogenetic implications and clinical applications. Journal of Cellular and Molecular Medicine (2019).
6. Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature. PLOS Genetics (2015).