Deletion of AT1a (Angiotensin II Type 1a) Receptor or Inhibition of Angiotensinogen Synthesis Attenuates Thoracic Aortopathies in Fibrillin1C1041G/+ Mice
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ABSTRACT:
PROVIDER: PRJNA1287542 | ENA |
REPOSITORIES: ENA
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Project description:Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+). Approach and Results: Thoracic aortic aneurysm in Fbn1C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1C1041G/+ females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1C1041G/+ mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1C1041G/+ mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathologies in the proximal thoracic aorta of male Fbn1C1041G/+ mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1C1041G/+ mice.
2025-07-07 | GSE301765 | GEO
Project description:S100A4-lineage Cells Contribute Modesty to Angiotensin II-mediated Thoracic Aortic Aneurysms Through Angiotensin II Type 1a Receptor in Mice
| PRJNA1333846 | ENA
Project description:Background: Angiotensin II (AngII) exerts a critical role in thoracic aortic aneurysm (TAA) formation via AngII type 1a receptor (AT1aR). However, the principal cell type mediating this process remains unclear. Our previous study demonstrated that S100A4-lineage cells are present in the aortic wall and involved in AngII-induced vascular remodeling. In the present study, we investigated whether S100A4-lineage cells contribute to AngII-mediated TAA formation through AT1aR. Methods: Proteomic, bulk RNA sequencing, and single-cell RNA sequencing data were analyzed to assess changes in S100A4 abundance in response to AngII infusion. Lineage tracing was performed to track S100A4-lineage cells during AngII-mediated TAA formation. Either saline or AngII was infused in mice with genetic deletion of AT1aR in S100A4-lineage cells and their wild-type littermates. Results: AngII infusion increased S100A4 protein and mRNA abundance significantly in the ascending aorta, particularly within smooth muscle cells and fibroblasts. Under basal conditions, S100A4-positive cells were localized to the media and adventitia. Following AngII infusion, these cells expanded markedly and populated the entire aortic wall. Deletion of AT1aR in S100A4-lineage cells modestly reduced AngII-induced TAA formation. Conclusions: S100A4-lineage cells modestly contribute to AngII-mediated TAA development through AT1aR in mice.
2026-01-01 | GSE309042 | GEO
Project description: Not available
| S-EPMC8458261 | biostudies-literature
Project description:Using Cdh5-Cre and Sm22-Cre transgenes to characterize the impact of disruption of the angiotensin II type 1a receptor (AT1ar) in vascular endothelial and smooth muscle cells, respectively, of wild type (WT) mice compared to fibrillin-1 hypomorphic mice (Fbn1mgR/mgR mice) that replicate early onset progressively severe Marfan syndrome (MFS) with dissecting thoracic aortic aneurysm (TAA).
2018-01-30 | GSE109797 | GEO
Project description:Angiotensinogen is the precursor of angiotensin II, a potent vasopressor in the renin-angiotensin-aldosterone system. Small interfering RNAs targeting hepatic angiotensinogen have been proven to be effective on blood pressure lowering in hypertension patients through reducing AGT levels in blood, and such effect could last over 6 months. Existing siRNA molecules has been high effective. However, it may be possible to develop novel siRNA molecules with improved inhibitory activity and longer duration period. In this study, we demonstrated an entire development process for a novel siRNA targeting hepatic angiotensinogen. Through proper combination of bioinformatics on-target/off-target screening on sequences, chemical modification patterns and liver-targeting delivery ligands, we have developed siRNA molecules with equivalent or better inhibitory activity, duration of effect and safety profile compared with siRNA molecules discovered previously. Furthermore, our analysis also revealed the correlation between efficacy and free energy of siRNAs. At present, no model can accurately predict the activity and off-target risk of fully modified siRNA molecules, thus efficient screening procedures are essential during the development of siRNA candidates. This study has provided a detailed and useful reference for the development of potent and safe siRNAs, which could also guide the future development of siRNAs on other targets.
2025-04-21 | GSE291523 | GEO
Project description:The brain renin-angiotensin system (RAS) stimulates resting metabolic rate in part through a mechanism involving suppression of the circulating RAS. This effect appears to be mediated through a reduction in angiotensin AT2 receptor (AT2R) signaling within inguinal fat. To examine the molecular mechanisms underlying this effect, mice with hyperactivity of the brain RAS (“sRA” mice, expressing human renin via the synapsin promoter and human angiotensinogen via its own promoter) and littermate controls were chronically infused with vehicle or the AT2R specific agonist, CGP-42112a (CGP, 90 ng/hr, 8 wk, sc). To identify altered signaling pathways, total RNA was isolated from inguinal adipose tissue and transcript abundance was quantitated by RNA-Seq.
2016-12-07 | GSE77214 | GEO
Project description:The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP), where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differently regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently unregulated genes, angiotensinogen, was validated using a in-situ hybridization. Angiotensinogen is the precursor of angiotensin II the main effector of the brain renin-angiotensin system (RAS), which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1)) antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain and ACTH release following maternal separation. AT(1) receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and identify signaling cascades, that control stress system activity in the neonate. Keywords: phenotype Litters were randomly assigned to either a maternally non-separated or 24 hour maternally separated condition. At the time of testing, all pups from a litter were sacrificed immediately by decapitation.
2010-05-16 | E-GEOD-14687 | biostudies-arrayexpress
Project description:The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP), where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differently regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently unregulated genes, angiotensinogen, was validated using a in-situ hybridization. Angiotensinogen is the precursor of angiotensin II the main effector of the brain renin-angiotensin system (RAS), which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1)) antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain and ACTH release following maternal separation. AT(1) receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and identify signaling cascades, that control stress system activity in the neonate. Keywords: phenotype
2009-07-22 | GSE14687 | GEO
Project description:Vascular smooth muscle cells (vSMC) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor-related protein 1 (LRP1), a large endocytic and signaling receptor that recognizes numerous ligands including ApoE-rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in v SMC (smLRP1-/- mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1-/- mice that are known to be induced by angiotensin II (AngII)-mediated signaling, suggesting that this pathway is dysregulated. Administration of losartan, an AngII type I receptor antagonist, or an angiotensinogen antisense oligonucleotide to reduce plasma angiotensinogen concentrations restored the normal SMA phenotype in smLRP1-/- mice and prevented aneurysm formation. Additionally, employing a vascular injury model, we noted excessive vascular remodeling and neointima formation in smLRP1-/- mice that was restored by losartan administration. Together, these findings reveal that LRP1 regulates vascular integrity and remodeling of the SMA by attenuating excessive AngII-mediated signaling.
2023-03-11 | PXD038236 | Pride