Sox9 is increased in arterial plaque and stenosis, associated with synthetic phenotype of vascular smooth muscle cells and causes alterations in extracellular matrix and calcification

Abstract

Vascular smooth muscle cells (VSMC) exhibit a dual role in progression and maintenance of arteriosclerosis. They are fundamental for plaque stability but also can drive plaque progression. During pathogenic vascular remodeling, VSMC transdifferentiate into a phenotype with enhanced proliferation and migration. Moreover, they exert an increased capacity to generate extracellular matrix proteins. A special lineage of transdifferentiated VSMC expresses Sox9, a multi-functional transcription factor. The aim of the study was to examine the role of Sox9 in phenotypic alterations leading to arteriosclerosis. Using mouse models for arterial stenosis, Sox9 induction in diseased vessels was verified. The phenotypic switch of VSMC from contractile to proliferative nature caused a significant increase of Sox9 expression. Various factors known to be involved in the progression of arteriosclerosis were examined for their ability to modulate Sox9 expression in VSMC. While PDGF-BB resulted in a strong transient upregulation of Sox9, TGF-β1 appeared to be responsible for a moderate, but prolonged increase of Sox9 expression. Beside the regulation, functional studies focused on knockout and overexpression of Sox9. A Sox9-dependent alteration of extracellular matrix could be revealed and was associated with an upregulated calcium deposition. Taken together, Sox9 is identified as important factor of VSMC function by modulation the extracellular matrix composition and calcium deposition, which are important processes in plaque development.

TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse

“…However, comparable to the M1 response, we found that several genes of the "Cellular Response to External Stimulus" pathway failed to be upregulated in the absence of Treml4. For example, Matrix metalloproteinase 9 (Mmp9) and SRY-Box Transcription Factor 9 (Sox9), both of which have been implicated in ECM deposition and mineralization (52)(53)(54) were lower in oxLDL-stimulated Treml4 −/− macrophages suggesting a mechanism whereby Treml4 might control plaque composition. Lastly, our oxLDL stimulations uncovered an unexpected mechanism by which Treml4 might be affecting lesion-associated inflammation.…”

Influence of caveolin-1 and endothelial nitric oxide synthase on adventitial inflammation in aortic transplants

“…3 These VSMCs migrate mainly from the media, and exhibit phenotypic plasticity that enables their transdifferentiation into macrophage -like or fibroblast -like cells. 4,5 In contrast, vascular inflammation can also promote a dilation of arteries resulting in coronary artery ectasia. 6 ABSTRACT BACKGROUND Restenosis after endovascular interventions is a clinically relevant process that is directly associated with increased morbidity.…”

The Interplay of WNT and PPARγ Signaling in Vascular Calcification

“…The main osteochondrogenic transcriptions factors SRY-box transcription factor 9 (SOX9) and runt-related transcription factor 2 (RUNX2, also known as CBFA1) are found in atherosclerotic plaques, being mainly expressed in osteochondrogenic VSMC [31][32][33][34]. These factors are essential during endochondral ossification, paving the way for MSC to differentiate to chondrocytes and, finally, to osteoblasts [11].…”

“…The dysregulation of this pathway in VSMC is well known to play a role in their osteochondrogenic differentiation, and BMP-2 was found to induce WNT signaling activity. Notably, the WNT signaling pathway is essential for endochondral ossification by controlling the osteochondrogenic transition of MSC-a mechanism similar to the osteochondrogenic transition of VSMC during VC [31][32][33][34]. In MSC, the PPARγ signaling pathway inhibits endochondral ossification by interfering with the WNT signaling pathways, and comparable crosstalk in VSMC seems plausible [48].…”

“…As mentioned in Section 1.2, calcified atherosclerotic plaques, as well as synthetic and osteochondrogenic VSMC, display expression of SOX9 and RUNX2. Both transcription factors are regulated through WNT signaling and as a consequence, numerous downstream genes-important for ECM remodeling and calcification-such as COL2A1, ACAN, OCN, and ALP are found in calcified lesions [31][32][33][34].…”