Saturday, May 17, 2025
5/17/2025
Mechano-epigenetic disruption in aortic aneurysm - PROJECT SUMMARY Thoracic aortic aneurysm (TAA) is a progressive dilation of the aorta induced by profound disorganization of the extracellular matrix and smooth muscle cell (SMC) dysfunction, which can lead to high morbidity and mortality complications (i.e., ruptures and dissections). Although recent single-cell RNAseq studies greatly informed SMC phenotypic evolution and TAA pathophysiology, no therapeutic avenues tested so far have demonstrated superior efficacy over prophylactic aortic replacement, which remains the primary option for patients with TAA. SMC mechanosensing (i.e., the ability of SMC to sense and transmit the vessel wall tension into the cell) disruption is believed to be a central driver of aortic dilation and SMC dysfunction and due to extracellular matrix degradation or focal adhesion defect. Yet, there are important unresolved questions. How does defect in SMC mechanosensing influence SMC phenotypic transitions, particularly SMC dedifferentiation? What are the mechano-dependent molecular and epigenetic pathways regulating SMC phenotype and function in TAA? The long-term objective of this project is to investigate how SMC mechanosensing influences nucleus and chromatin organization and identify mechano-dependent epigenetic mechanisms whose alterations drive TAA-promoting phenotypes and aortic dilation. Our preliminary studies identify histone modification H3K4me2 genomic distribution alterations in SMC as a common feature in human and murine TAA, irrespective of etiology or experimental model. We have recently demonstrated that H3K4me2 governs SMC lineage identity and contractile state, suggesting that loss of H3K4me2 could drive SMC dysfunction in TAA. We also found that disruption of the interaction between the actin cytoskeleton and the nucleus causes similar H3K4me2 alterations and a marked chromatin reorganization. Thus, we hypothesize that nuclear mechanosensing plays a critical role in maintaining SMC contractile state. Disruption of the ECM-Cytoskeleton-Nucleus axis encountered in TAA drives chromatin reorganization and epigenetic reprogramming, including H3K4me2 redistribution causing SMC dedifferentiation and dysfunction. Our central hypothesis will be tested by employing a multidisciplinary approach ranging from epigenomics to biomechanics analysis in cultured cell systems, novel epigenome editing mouse models, and human specimens. Aim 1 will test the hypothesis that loss of H3K4me2 drives aortic dilation by inducing SMC dedifferentiation and TAA- promoting phenotypes. Aim 2 will test the hypothesis that nuclear tension controls chromatin organization consistent with SMC differentiation and contractility. Aim 3 will determine if the disruption of focal adhesion mediated-mechanosensing drives aortic dilation by triggering chromatin remodeling promoting SMC transition to TAA-promoting phenotypes. This proposal will greatly enhance our understanding of external and cellular pathways influencing SMC function through regulation of epigenetic programming. It could translate to the identification of new therapeutic strategies for protection against aortic dilation.
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