Exploring Origin-dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases via Intersectional Genetics
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PROVIDER: PRJNA1168885 | ENA |
REPOSITORIES: ENA
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Project description:The developmental heterogeneity of smooth muscle cells (SMCs) plays a crucial role in the prevalence of segment-specific aortic diseases. Traditional genetic tools, however, are insufficient for in vivo analysis of disease susceptibility associated with cellular origin. To overcome this challenge, we engineered a state-of-the-art dual recombinase-mediated intersectional genetic system, tailored to precisely target SMCs from distinct developmental origins. Employing this system, we selectively knocked out Tgfbr2 in the ascending aorta and Smad4 in the aortic arch. Our results distinctly demonstrate the indispensable roles these genes play in sustaining SMC integrity across different aortic segments. This advanced genetic system not only deepens our understanding of aortopathies but also significantly enhances the potential for modeling and elucidating the mechanisms driving segment-specific aortic diseases.
2024-10-05 | GSE278774 | GEO
Project description:Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to stiffness and dysfunction. Based on shared risk factors and end stage pathologies, calcific aortic valve disease (CAVD) and coronary artery calcification (CAC) are often considered as one disease, and similarly treated. However, the clinical conditions associated with each phenotype can be different, suggesting multifaceted pathologies. To better understand diversity in molecular and cellular processes that underlie calcification in vascular and valvular structures, we exposed aortic vascular smooth muscle cells (AVSMCs) and aortic valve interstitial cells (AVICs) to calcific stimuli including high (2.5mM) phosphate and osteogenic media (OM) treatments in vitro. Consistent with clinical observations made by others, we show that AVSMCs are more susceptible to calcification than AVICs, and this process is mediated by cell-specific and treatment-specific molecular responses. RNA-seq analysis demonstrates that in response to calcific-stimuli, both AVSMCs and AVICs activate a robust ossification-program, although the signaling pathways, cellular processes and osteogenic-associated markers involved are diverse. In addition, VIC-mediated calcification appears to involve biological processes related to osteo-chondro differentiation and down regulation of actin cytoskeleton genes, that are not observed in VSMCs. Furthermore, are findings suggest that signaling pathways involved in cardiovascular cell calcification are dependent on the calcific-stimuli, including a requirement of PI3K signaling for OM-induced calcification, and not 2.5mM Phosphate. Together, this study provides a wealth of information suggesting that the pathogenesis of cardiovascular calcifications may be significantly more diverse than previously appreciated.
2023-08-01 | GSE227131 | GEO
Project description:Aortic diseases are a rare but potentially life-threatening condition. We present a serum proteomic study for a spectrum of aortic diseases including thoracic aortic aneurysms (n = 11), chronic dissections (n = 9), acute aortic dissections (n = 11), and surgically treated dissections (n = 19) as well as healthy controls (n = 10) and patients of coronary heart disease (n = 10) to represent non-aortic cardiovascular disease. In total, we identified and quantified 425 proteins across all 70 samples. The different aortic diseases represented distinguishable proteome profiles. We identified protein clusters that positively or negatively correlate with disease severity, including increase of cytosolic tissue leakage proteins and decrease of components of the coagulation and complement system. Further, we identified a serum proteome fingerprint of acute aortic dissections, consisting, among others, of enriched inflammatory markers such as C-reactive protein and members of the S100 protein family. The study underlines the applicability of serum proteomics for the investigation of aortic diseases and highlights the possibility to establish disease-specific prognostic markers.
| EGAS00001006201 | EGA
Project description:Aortic single-cell RNA sequencing data from second heart field lineage traced mice with Fbn1C1041G/+ and control mice.
2022-06-15 | GSE186845 | GEO
Project description:Calcific Aortic Valve Disease (CAVD) is a common heart valve condition, often characterized by severe narrowing of the aortic valve. It lacks pharmaceutical treatments and typically requires aortic valve replacement surgery, imposing a significant burden on healthcare resources.This study reports the expression profile of circRNAs in the aortic valve tissues of CAVD patients and a normal control group (non-CAVD). We collected aortic valve tissue samples from three CAVD patients who underwent aortic valve replacement surgery due to severe aortic valve stenosis, as well as aortic valve samples from non-CAVD patients who either received heart transplant surgery (recipient heart) or had their aortic valve removed due to aortic dissection. Overall, our research reveals the significant role of circRNAs in the progression of CAVD. CircRNAs, a class of circular non-coding RNA molecules, are actively studied for their functions and regulatory mechanisms within cells. These findings contribute to a deeper understanding of the molecular mechanisms underlying CAVD, particularly the potential involvement of circRNAs in this disease.
2024-02-02 | GSE254393 | GEO
Project description:Alveolar type 2 (AT2) cells are stem cells of the alveolar epithelia. Previous genetic lineage tracing studies reported multiple cellular origins for AT2 cells after injury. However, conventional lineage tracing based on Cre-loxP has the limitation of non-specific labeling. Thus, the exact contribution of various epithelial cells to the pools of AT2 cells under different conditions remains unclear. Here, we used dual recombinases-mediated intersectional genetic lineage tracing to investigate the cellular origins of AT2 cells during lung homeostasis, injury and repair. In contrast to previous studies, we found AT1 cells were terminally differentiated cells and did not contribute to AT2 cells after lung injury and repair. Distinctive, but simultaneous, labeling of club cells, bronchioalveolar stem cells (BASCs), and AT2 cells revealed the exact contribution of each to AT2 cells after lung injury. Moreover, we found that club cells have the potential to rebuild virtually all alveoli in some severely injured lung regions. Mechanistically, Notch signaling promotes a BASCs-to-AT2 cell transition, but it inhibits club cell-to-AT2 cell conversion during lung repair. This intersectional genetic lineage tracing strategy with enhanced precision allowed us to elucidate the physiological role of AT1, club, BASCs, and AT2 cells to alveolar regeneration after injury.
2024-01-06 | GSE252588 | GEO
Project description:Aortic valve calcific disease (CAVD) is a common heart valve condition typically characterized by severe narrowing of the aortic valve. Our previous research has shown that circHIPK3 is downregulated in calcified aortic valve tissues and plays a role in regulating the progression of CAVD. To further investigate how circHIPK3 exerts its inhibitory effects on aortic valve calcification, we overexpressed circHIPK3 in aortic valve interstitial cells and conducted RNA-seq analysis, revealing that circHIPK3 regulates key factors in the Wnt signaling pathway. These findings contribute to a deeper understanding of the molecular mechanisms underlying CAVD, particularly the potential involvement of circRNAs in this disease.
2024-02-02 | GSE254394 | GEO
Project description:Exploring molecular profiles of calcification in aortic vascular smooth muscle cells and aortic valvular interstitial cells
| PRJNA943271 | ENA
Project description:and with higher incidence if associated to bicuspid aortic valve (BAV) for unknown reasons. TAA is usually diagnosed fortuitously and the lack of effective drug therapy to delay progression and avoid dissection lies in the limited knowledge of pathophysiology. Objectives. We aimed to identify the molecular hallmarks that difference the aortic dilatation associated to bicuspid (BAV) and tricuspid aortic valve (TAV) patients while setting plasma diagnostic molecular panels valve-associated. Methods. Sporadic TAA patients and control subjects (n=91) were classified according to valve type (BAV, TAV). Vascular smooth muscle cells isolated from TAA patients’ aortas were firstly analyzed by mass spectrometry based high-throughput proteomics according to valve type. Extracellularly secreted proteins were secondly analyzed in plasma from TAA patients versus control subjects as diagnostic candidates. Results. Aneurysmal aortas from BAV patients showed a stress phenotype, weakened extracellular matrix interactions, DNA damage and affected protein homeostasis compared to TAV patients. Two plasma marker panels of sporadic TAA valveassociated were identified, showing significant correlation with aortic diameter for C1QTNF5, LAMA2, and SPARC proteins, in BAV patients, and for CP and FAP proteins, in TAV patients. Conclusions. The arterial wall of BAV patients shows a limited capacity to counteract drivers of sporadic TAA while resembling aged arteries.The molecular pathways identified here support the need of differential molecular diagnosis and therapeutic approaches for BAV and TAV patients.
2024-10-17 | PXD043062 | Pride
Project description:Aortic valve calcifications are often associated with calcium deposition and tissue mineralization, resulting in stiffness and dysfunction. To better understand the diversity of molecular and cellular processes for calcification in valve structures, we isolated human aortic valve interstitial cells (AVICs) and exposed them to calcification stimulation. RNA-seq revealed that in response to calcified stimuli, AVIC activates a robust ossification program, although the signaling pathways, cellular processes, and osteogenesis-related markers involved are diverse. In conclusion, this study provides a wealth of information suggesting that the pathogenesis of aortic valve calcification may be much more than previously understood.
2024-01-03 | GSE252266 | GEO