Habitual Exercise Modulates Neuro-Immune Interaction to Mitigate Aortic Stiffness
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ABSTRACT:
PROVIDER: PRJNA1235313 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32671477.fastq.gz | Fastqsanger.gz | |||
| SRR32671478.fastq.gz | Fastqsanger.gz | |||
| SRR32671479.fastq.gz | Fastqsanger.gz |
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Project description:Exercise augments hemodynamic shear to activate mechano-sensitive molecular transducers in the vascular endothelium. Recently, the central nervous system has been reported to mediate neuro-immune interaction in the aortic adventitia (AA). Whether exercise modulates the sympathetic nerve interaction with the immune cells to mitigate aortic stiffness remains unknown. Four weeks of Angiotensin II (Ang II) infusion to C57BL/6 mice increased neural activation to increase the expression of tyrosine hydroxylase (TH) for sympathetic nerve axons and norepinephrine levels along with the colocalization of synapsin and β2-adrenergic receptor (β2-AR) positive macrophages in the AA. This Ang II-mediated sympathetic nerve and macrophage interaction activated fibroblasts to increase vascular fibrosis and arterial pulse wave velocity (PWV). Sympathetic denervation with celiac ganglionectomy or 6-hydroxydopamine treatment abrogated Ang II-mediated TH+, AA thickness, and PWV. scRNAseq analyses of the AA revealed that Ang II increased the circulating monocyte-derived macrophages (Ccr2+CD80) but reduced the resident macrophages (Lyve1+CD163). Gene ontology analysis of differentially expressed genes unveiled that voluntary wheel running (VWR) mitigated Ang II-mediated increase in Ccr2+CD80 macrophages, cytokines-mediated signaling pathways in macrophages, and extracellular matrix deposition in fibroblasts. Macrophage depletion with Ki20227 (colony stimulating factor-1 receptor inhibitor) reduced Ang II-mediated synapsin+ macrophages. Using the Ccr2 knock-in (Ccr2GFP) / knock-out (Ccr2KO) mice, we observed that Ang II-mediated increases in Ccr2+ macrophages were expressed in Ccr2GFP mice but were absent in Ccr2KO mice. Also, Ang II-induced increases in synapsin expression, neighboring Ccr2+ cells, AA thickness, and PWV were reduced in Ccr2KO mice. Both Ki20227 and Ccr2KO reduced the Ang II-mediated increase in TH levels. Furthermore, VWR-mediated reduction in vascular fibrosis and aortic stiffness were mitigated by a β2-AR agonist, terbutaline, indicating β2-AR in neuro-immune modulation. Exercise mitigates Ang II-mediated sympathetic axon interaction with the circulating monocyte-derived macrophages in the AA to attenuate vascular fibrosis and aortic stiffness.
2025-04-11 | GSE291831 | GEO
Project description:BACKGROUND: Previous genomic studies with human tissues have compared differential gene expression between 2 conditions (ie, normal versus diseased) to identify altered gene expression in a binary manner; however, a potentially more informative approach is to correlate the levels of gene expression with quantitative physiological parameters. METHODS AND RESULTS: In this study, we have used this approach to examine genes whose expression correlates with arterial stiffness in human aortic specimens. Our data identify 2 distinct groups of genes, those associated with cell signaling and those associated with the mechanical regulation of vascular structure (cytoskeletal-cell membrane-extracellular matrix). Although previous studies have concentrated on the contribution of the latter group toward arterial stiffness, our data suggest that changes in expression of signaling molecules play an equally important role. Alterations in the profiles of signaling molecules could be involved in the regulation of cell cytoskeletal organization, cell-matrix interactions, or the contractile state of the cell. CONCLUSIONS: Although the influence of smooth muscle contraction/relaxation on arterial stiffness could be controversial, our provocative data would suggest that further studies on this subject are indicated. Keywords: other
2003-08-28 | GSE420 | GEO
Project description:BACKGROUND: Previous genomic studies with human tissues have compared differential gene expression between 2 conditions (ie, normal versus diseased) to identify altered gene expression in a binary manner; however, a potentially more informative approach is to correlate the levels of gene expression with quantitative physiological parameters. METHODS AND RESULTS: In this study, we have used this approach to examine genes whose expression correlates with arterial stiffness in human aortic specimens. Our data identify 2 distinct groups of genes, those associated with cell signaling and those associated with the mechanical regulation of vascular structure (cytoskeletal-cell membrane-extracellular matrix). Although previous studies have concentrated on the contribution of the latter group toward arterial stiffness, our data suggest that changes in expression of signaling molecules play an equally important role. Alterations in the profiles of signaling molecules could be involved in the regulation of cell cytoskeletal organization, cell-matrix interactions, or the contractile state of the cell. CONCLUSIONS: Although the influence of smooth muscle contraction/relaxation on arterial stiffness could be controversial, our provocative data would suggest that further studies on this subject are indicated.<br><br>Note that files GSM6179.txt and GSM6182.txt as imported from GEO are identical.
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Project description:SMCs express plasminogen activator inhibitor-1 (PAI-1), which regulates SMC function and vascular remodeling. However, whether PAI-1 controls SMC cytoskeletal dynamics and stiffness is unknown, and the causal role of PAI-1 in arterial stiffening is undefined. SMCs from human coronary arteries and aortae of wild-type vs. PAI-1-deficient mice were cultured with or without PAI-039, a specific PAI-1 inhibitor, after which cell stiffness was measured by atomic force microscopy, filamentous actin structures were assessed by confocal microscopy, and the activities cofilin, LIM domain kinase 1 (LIMK), slingshot homolog 1 (SSH), and AMP-activated protein kinase (AMPK) were measured. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. Effects of PAI-039 on aortic stiffness were assessed by pulse wave velocity. PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by significant decreases in cytoplasmic actin filaments. Similar effects were observed in wild-type, but not in PAI-1-deficient SMCs. Mechanistically, PAI-039 significantly increased the activity of cofilin, an actin depolymerase, in SMCs expressing PAI-1, but not in PAI-1-deficient cells. PAI-039 had no significant effects on LIMK or SSH activity. RNA-sequencing analysis suggested that PAI-039 up-regulates AMPK signaling in SMCs, which was confirmed by western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness without significantly altering peri-aortic fibrosis. PAI-039 decreases intrinsic SMC stiffness by reducing cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacologic inhibition of PAI-1 has potential to treat cardiovascular diseases mediated by accelerated arterial stiffening.
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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.
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Project description:Wood stiffness is the most important wood quality trait of forest trees for structural timber production. We investigated genes differentially transcribed in radiate pine trees with distinct wood stiffness using bulked segregant analysis (BSA) and cDNA microarrays. Transcript accumulation in earlywood (EW) and latewood (LW) of high (HS) and low stiffness (LS) trees in two progeny trials was compared. Radiata pine trees used for microarray experiment were selected from two progeny trials planted at Flynn and Kromelite, Australia. Based on the IML-based MOE measurement, five families with highest and lowest MOE each were selected from each trial, which represented two segregant populations with contrasting wood stiffness. Two individuals from each selected family were further sampled. Developing xylem tissues of selected trees in Flynn trial were sampled in spring (October) and autumn (April), representing earlywood (EW) and latewood (LW) of juvenile aged trees, respectively. Collection of xylem tissues from Kromelite trial was arranged in summer (late November) when latewood (LW) was formed. The xylem tissues were scraped at breast height with a sharp chisel after the bark was removed. In Flynn trial EW and LW tissues were collected from the same sampled trees on opposite sides of the trunk. Transcript accumulation was compared in trees with highest (HS) and lowest stiffness (LS) using xylem samples from Flynn collected in spring (EW) and autumn (LW), as well as Kromelite in summer (LW), respectively. Bulked segregant analysis (BSA) was used for the experiment design. Total RNA samples extracted from the five trees with HS were pooled at equal amount, and compared to the bulked five individuals with LS. This pooling strategy can partly minimize the genetic variation among different genotypes. Dye swaps were applied in each biological replicate.
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