Project description:Blood flow within the vasculature is a critical determinant of endothelial cell (EC) identity and functionality, yet the intricate interplay of various hemodynamic forces and their collective impact on endothelial and vascular responses are not fully understood. Specifically, the role of hydrostatic pressure in the context of flow response is understudied, despite its known significance in vascular development and disease. To address this gap, we developed in vitro models to investigate how pressure influences EC responses to flow. Our study demonstrates that elevated pressure conditions significantly modify shear-induced flow alignment and increase endothelial cell density, a phenomenon often observed in vascular diseases. Utilizing both bulk and single-cell RNA sequencing, we found that while flow is the primary driver of transcriptional changes from static conditions, pressure distinctly modulates this flow response by upregulating gene sets linked to arterial cell phenotypes. Conserved pressure-responsive transcriptional signatures identified in human ECs were upregulated during the onset of circulation in early mouse embryonic vascular development, where pressure was notably associated with transcriptional programs essential to arterial and hemogenic EC fates. Our findings emphasize the necessity of an integrative approach to endothelial cell mechanotransduction, one that encompasses the effects induced by pressure alongside other hemodynamic forces.
Project description:We carried out a genome-wide association and replication study for blood pressure in a two-stage approach (max N = 289,038) with a discovery stage sample of 130,777 East Asian individuals, identifying 19 new genetic loci. We found a significant genetic heterogeneity between East Asian and European-descent populations at several blood pressure loci, conforming to “a common ancestry-specific variant association model”. At 6 unique loci, distinct non-rare (or common) ancestry-specific variants co-localized within the same linkage disequilibrium block despite the significantly discordant direction of effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect sizes is 0.898 and 0.851 for systolic and diastolic blood pressure, respectively. Some of the ancestry-specific association signals were also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in the occurrence of ethnic differences in complex traits such as blood pressure.
Project description:Genome-wide association studies (GWAS) have identified blood pressure-related loci, but functional insights into causality and related molecular mechanisms lag behind. We functionally characterize 4608 genetic variants in linkage with blood pressure loci in vascular smooth muscle cells (VSMCs) and cardiomyocytes (CMs) by massively parallel reporter assays (MPRAs). Regulatory variants are in non-conserved loci, enriched in repeats, and alter trait-relevant transcription factor binding sites. Higher-order genome organization indicates that loci harboring regulatory variants converge in spatial hubs to control specific signaling pathways required for proper cardiovascular function. Modelling different variant allele frequencies by CRISPR prime editing led to expression changes of KCNK9, SFXN2, and PCGF6. We provide mechanistic insights into how regulatory variants converge their effects on blood pressure genes (i.e. ULK4, MAP4, CFDP1, PDE5A, 10q24.32), and cardiovascular pathways. Our findings support advances in molecular precision medicine to define functionally relevant variants and the genetic architecture of blood pressure genes.
Project description:The genetic response of E.coli K-12 MG 1655 to 1MPa pressure was examined using transcriptomic analysis by RNA-Seq. The results show many differentially expressed genes are invovled in oxidative stress, Fe-S cluster assesmbly and iron acquisition.
Project description:A mid-thoracic aorta coarcted rat was created to generate a stable pressure difference above versus below the coarctation ligature. This study determined that the PVAT around the thoracic aorta exposed to a higher pressure has a significantly reduced ability to assist stress relaxation versus that below the ligature and appears to retain the ability to be anticontractile. At the same time, the PVAT around the thoracic aorta exposed to higher pressure had a reduced adipogenic potential versus that below the ligature. Transcriptomics analyses indicated that PVAT below the coarctation showed the greatest number of DEGs with an increased profile of the synaptic neurotransmitter gene network.
Project description:Genome-wide association studies (GWAS) have identified blood pressure-related loci, but functional insights into causality and related molecular mechanisms lag behind. We functionally characterize 4608 genetic variants in linkage with blood pressure loci in vascular smooth muscle cells (VSMCs) and cardiomyocytes (CMs) by massively parallel reporter assays (MPRAs). Regulatory variants are in non-conserved loci, enriched in repeats, and alter trait-relevant transcription factor binding sites. Higher-order genome organization indicates that loci harboring regulatory variants converge in spatial hubs to control specific signaling pathways required for proper cardiovascular function. Modelling different variant allele frequencies by CRISPR prime editing led to expression changes of KCNK9, SFXN2, and PCGF6. We provide mechanistic insights into how regulatory variants converge their effects on blood pressure genes (i.e. ULK4, MAP4, CFDP1, PDE5A, 10q24.32), and cardiovascular pathways. Our findings support advances in molecular precision medicine to define functionally relevant variants and the genetic architecture of blood pressure genes.
Project description:Reactive astrocytes are typically studied in models that cause irreversible mechanical damage to axons, neuronal cell bodies, and glia. We evaluated the response of astrocytes in the optic nerve head to a subtle injury induced by a brief, mild elevation of the intraocular pressure. Astrocytes demonstrated reactive remodeling showing hypertrophy, process retraction and simplification of their shape. We used microarray to indentify differentially expressed genes and to investigate the molecular mechanisms of astrogliosis in response to this subtle injury. Six- to eight-week old C57Bl/6 male mice were used in this experiment. One eye underwent an elevation in intraocular pressure to 30 mmHg for 1 hour and then allowed to recover for 3 days. The contralateral eye served as a control. Due to the small tissue size of the mouse optic nerve head, two optic nerve heads were pooled together for each microarray chip. We used 10 mice to generate five biological replicates for each condition.
Project description:Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4 +CD44hiCD62L lo T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide.
Project description:<p><strong>BACKGROUND/AIMS:</strong> Phaeodactylum tricornutum, a model organism of diatoms, plays a crucial role in Earth's primary productivity. Investigating its cellular response to grazing pressure is highly significant for the marine ecological environment. Furthermore, the integration of multi-omics approaches has enhanced the understanding of its response mechanism. </p><p><strong>METHODS:</strong> To assess the molecular and cellular responses of P. tricornutum to grazer presence, we conducted transcriptomic, proteomic and metabolomic analyses, combined with phenotypic data from previous studies. Sequencing data were obtained by Illumina RNA sequencing, TMT Labeled Quantitative Proteomics and Non-targeted Metabolomics, and WGCNA analysis and statistical analysis were performed.</p><p><strong>RESULTS:</strong> Among the differentially expressed genes, we observed complex expression patterns of the core genes involved in the phenotypic changes of P. tricornutum under grazing pressure across different strains and multi-omics datasets. These core genes primarily regulate the levels of various proteins and fatty acids, as well as the cellular response to diverse signals. </p><p><strong>CONCLUSION:</strong> Our research reveals the association of multi-omics in four strains responses to grazing effects in P. tricornutum. Grazing pressure significantly impacted cell growth, fatty acid composition, stress response, and the core genes involved in phenotype transformation.</p>