Retinoic Acid Signaling in Vascular Smooth Muscle Dynamics

Retinoic acid, a metabolite of vitamin A, exerts profound control over vascular smooth muscle cell behaviour through activation of nuclear retinoic acid receptors. In healthy vessels, smooth muscle cells adopt a contractile phenotype that maintains vessel tone and structural integrity. In response to injury or inflammatory cues, these cells switch to a synthetic phenotype, characterised by enhanced proliferation, migration and extracellular matrix production. Retinoic acid signalling intervenes at multiple levels of this phenotypic transition. Ligand‐bound receptors modulate transcription factors such as Krüppel‐like factor 4, repress cyclin-dependent kinases and engage key kinase pathways including AMPK, PI3K/Akt and mTOR. The net effect is restraint of neointimal hyperplasia, stabilisation of plaque architecture and preservation of endothelial function. Ongoing research explores how selective receptor agonists might be harnessed to prevent restenosis and atherosclerosis with minimal off-target effects.

Research from Nature Portfolio

Recent studies have demonstrated that all-trans retinoic acid ameliorates atherosclerotic lesion development by altering the perivascular microenvironment. In a murine model lacking apolipoprotein E, treatment promoted browning of perivascular adipose tissue and enhanced local adiponectin synthesis, both of which are associated with reduced smooth muscle cell migration into the intima. Simultaneously, retinoic acid increased nitric oxide availability in the vascular wall, contributing to improved endothelial-smooth muscle crosstalk and attenuation of inflammatory cytokine release.

Retinoic Acid Signaling in Vascular Smooth Muscle Dynamics publication trend

The graph below shows the total number of articles in retinoic acid signaling in vascular smooth muscle dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Retinoic acid: A bioactive derivative of vitamin A that binds nuclear receptors to regulate gene transcription.

Vascular smooth muscle cell (VSMC): A specialised muscle cell in the vessel wall responsible for contraction and structural support.

Phenotypic switching: The process by which VSMCs transition between contractile and synthetic states.

Neointimal hyperplasia: The thickening of the innermost vessel layer due to VSMC proliferation and migration.

Retinoic acid receptor (RAR): A nuclear receptor that mediates the genomic actions of retinoic acid.

AMPK (AMP-activated protein kinase): A cellular energy sensor that inhibits anabolic signalling and proliferation when activated.

mTOR (mechanistic target of rapamycin): A kinase central to cell growth and protein synthesis, often downregulated by retinoic acid signalling.

References

1. The Effect of Retinoids in Vascular Smooth Muscle Cells: From Phenotyping Switching to Proliferation and Migration. International Journal of Molecular Sciences (2024).
2. Upregulation of Nitric Oxide Production in Vascular Endothelial Cells by All-trans Retinoic Acid Through the Phosphoinositide 3-Kinase/Akt Pathway. Circulation (2005).
3. All-Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway. Frontiers in Pharmacology (2019).
4. All-trans-retinoic acid ameliorates atherosclerosis, promotes perivascular adipose tissue browning, and increases adiponectin production in Apo-E mice. Scientific Reports (2021).
5. Retinoic Acid Receptor α Mediates All-trans-retinoic Acid-induced Klf4 Gene Expression by Regulating Klf4 Promoter Activity in Vascular Smooth Muscle Cells*. Journal of Biological Chemistry (2012).