How do changes in the microenvironment influence the phenotypic transition of smooth muscle cells (SMCs) from contractile to synthetic cells, and how does this impact cardiovascular health? Or?

Changes in the microenvironment can significantly influence the phenotypic transition of smooth muscle cells (SMCs) from a contractile to a synthetic state. The microenvironment includes various factors such as mechanical stress, biochemical signals, extracellular matrix (ECM) composition, and inflammatory mediators. We specifically focused on the ECM in our publication because collagen, elastin, and fibronectin provide structural support and function as signaling molecules. They also play an important role in the stability of atherosclerotic plaques. Changes in ECM composition can activate signaling pathways that promote synthetic phenotypes. Targeting pathways involved in the regulation of SMC phenotype holds promise for the development of new treatments for cardiovascular diseases. Strategies that modulate the SMC phenotype toward a more contractile state may help prevent or reverse pathological vascular remodeling and improve cardiovascular outcomes.

Can you describe the methodology used to investigate genetic mutations that control extracellular matrix (ECM) secretion in SMCs and predict proteins associated with vascular disease?

We conducted a comprehensive study on the genetic regulation of extracellular matrix (ECM) secretion by smooth muscle cells (SMCs) and its impact on vascular diseases. We isolated human aortic SMCs from 123 multi-ancestral healthy heart transplant donors, cultured them, and measured the amount of secreted proteins using liquid chromatography and tandem mass spectrometry. We quantified 270 ECM and related proteins. We then performed protein quantitative trait locus (pQTL) mapping to identify loci associated with variation in protein abundance. We then performed functional annotation of these loci through a colocalization approach. This helped prioritize genetic variants potentially associated with vascular disease risk. For example, this approach highlighted that the A allele of the rs6739323 variant at the 2p22.3 locus was associated with decreased LTBP1 expression in SMCs and increased risk of atherosclerosis and calcification. This multifaceted methodology integrates proteomic analysis and genetic mapping to identify important proteins and genetic variants that may serve as novel therapeutic targets for vascular diseases.

Could you please elaborate on the specific protein LTBP1 and its potential impact in improving plaque stability?

We identified LTBP1 (latent transforming growth factor beta-binding protein 1) as an important protein in our study for its potential role in atherosclerotic plaque stability. The A allele of the genetic variant rs6739323 at the 2p22.3 locus is associated with decreased LTBP1 expression in smooth muscle cells (SMCs) and atherosclerosis-prone regions and is associated with increased risk of SMC calcification. It’s correlated. LTBP1 is abundant in SMCs and its decreased expression is associated with progressive and unstable atherosclerotic plaque lesions, suggesting its important role in maintaining plaque integrity. Previous studies support the involvement of LTBP1 in ECM organization and TGF-β activation, which is important for fibrotic cap formation and stability. Therefore, understanding the regulation and function of LTBP1 may provide insight into strategies to increase plaque stability, prevent plaque rupture, and reduce the risk of cardiovascular events.

What potential therapeutic targets have been identified to accelerate translational research in cardiovascular disease treatment?

Our study focuses on proteins associated with extracellular matrix (ECM) secretion by smooth muscle cells (SMCs) and identifies several potential treatments to accelerate translational research in cardiovascular disease treatment. Target identified. Among these, LTBP1 (latent transforming growth factor beta-binding protein) is of interest as it is associated with decreased expression in SMCs and atherosclerosis-prone regions and correlates with increased SMC calcification risk. It has been. We identified 20 additional loci associated with secreted protein abundance in SMCs, providing a broader range of potential targets. These findings raise the possibility of novel approaches aimed at increasing plaque stability and preventing cardiovascular events by targeting gene- and protein-level mutations that affect ECM composition and function within vascular tissues. This paves the way for the development of therapeutic strategies.

What challenges might researchers face in translating these discoveries into clinical applications?

Translating our findings into clinical applications may face several challenges, including the complexity of genetic regulation of protein secretion and its impact on vascular diseases. The specificity of the effects of genetic variant rs6739323-A on LTBP1 expression and plaque stability needs to be thoroughly validated in additional model systems. The multifactorial nature of cardiovascular disease makes direct application of single-target interventions difficult. Furthermore, developing therapies that modulate ECM composition without disrupting essential physiological processes has become a major challenge. These factors emphasize the need for extensive preclinical and clinical research to ensure safety and efficacy.

This study Atherosclerosis, thrombosis, and vascular biology.