An ncBAF-ETS2 Chromatin-Remodelling Axis Drives Vascular Smooth Muscle Cell Osteogenic Reprogramming in Vascular Calcification
Introduction: Vascular calcification is a detrimental ageing-related pathology that is markedly accelerated in metabolic disorders. It is driven by osteogenic differentiation of vascular smooth muscle cells (VSMCs), however epigenetic regulatory pathways activated early in this transition remain poorly defined. Methods: An in vitro calcification model was developed using primary human aortic…
Vascular calcification, an age-related disease exacerbated by metabolic disorders, is propelled by the transformation of vascular smooth muscle cells (VSMCs) into osteogenic cells. The precise epigenetic mechanisms that catalyze this transition are still largely unknown. To unravel this complex process, researchers established an in vitro calcification model using primary human aortic VSMCs cultured either with or without mineral stress.
They then examined epigenetic alterations through targeted PCR arrays and CUT&RUN sequencing. The outcomes of their transcriptomic and CUT&RUN analyses revealed that gene expression patterns were altered by epigenetic remodeling, suggesting that ncBAF (nuclear bromodomain-containing protein 5) and ETS2 (ETS family transcription factor 2) were implicated in this process.
During the initial stages of calcification triggered by mineral stress, SWI/SNF chromatin remodeling complexes began to shift towards ncBAF enrichment in pre-osteogenic VSMCs. ncBAF complexes were found to activate transcriptional programs associated with inflammation, apoptosis, and glycolysis - all characteristic features of calcifying VSMCs.
Furthermore, ETS2 emerged as a critical component of ncBAF complexes. Researchers discovered that ETS2 expression was regulated by ncBAF, forming a positive feedback loop that encouraged VSMC phenotypic switching. The co-activation of ETS2 and ncBAF led to a significant transcriptional shift, which was validated in human arterial single-cell datasets, where osteogenic/inflammatory clusters displayed NFκB and RUNX2 activation.
Spatial transcriptomics provided additional evidence that a macrophage-rich microenvironment might promote VSMCs towards an overt osteogenic/inflammatory phenotype. Immunohistochemistry further confirmed that ETS2 levels were correlated with the severity of calcification in human vessels, hinting at the potential clinical significance of ETS2.
This study uncovers a novel epigenetic mechanism in vascular calcification, where the ncBAF-ETS2 axis drives VSMC phenotypic switching. This finding opens up a new avenue for therapeutic intervention targeting VSMC plasticity to potentially halt the progression of cardiovascular calcification.
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