Similar Datasets
Project description:The adrenal cortex is characterized by a distinct architecture as well as a high density of specialized sinusoidal blood vessels. The preservation of this particular endothelial cell phenotype is likely vital for proper adrenal gland function. The aldosterone-producing zona glomerulosa harbors macrophages in close association with sinusoidal capillaries. However, the function of this macrophage-endothelial cell-juxtaposition in steady-state conditions is unknown. We show that macrophages preserve capillary specialization in the adrenal gland and modulate aldosterone secretion. By combining macrophage-specific deletion of the angiogenic cytokine Vascular Endothelial Growth Factor A (VEGF-A), single-cell transcriptomics and functional phenotyping, we provide evidence that loss of VEGF-A in myeloid cells, including adrenal gland macrophages depletes a specialized subset of PLVAP+ fenestrated endothelial cells in the zona glomerulosa of mice, along with increased deposition of basement membrane collagen IV and in
2024-06-24 | GSE245128 | GEO
Project description:The adrenal cortex is characterized by a distinct architecture as well as a high density of specialized sinusoidal blood vessels. The preservation of this particular endothelial cell phenotype is likely vital for proper adrenal gland function. The aldosterone-producing zona glomerulosa harbors macrophages in close association with sinusoidal capillaries. However, the function of this macrophage-endothelial cell-juxtaposition in steady-state conditions is unknown. We show that macrophages preserve capillary specialization in the adrenal gland and modulate aldosterone secretion. By combining macrophage-specific deletion of the angiogenic cytokine Vascular Endothelial Growth Factor A (VEGF-A), single-cell transcriptomics and functional phenotyping, we provide evidence that loss of VEGF-A in myeloid cells, including adrenal gland macrophages depletes a specialized subset of PLVAP+ fenestrated endothelial cells in the zona glomerulosa of mice, along with increased deposition of basement membrane collagen IV and induction of sub-endothelial fibrosis.
2024-06-24 | GSE245127 | GEO
Project description:Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure
| PRJNA1026981 | ENA
Project description:Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure (scRNA-Seq)
| PRJNA1026985 | ENA
Project description:Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure (bulk RNA-Seq)
| PRJNA1026986 | ENA
Project description:Primary and secondary hypertension are major risk factors for cardiovascular disease, the leading cause of death worldwide. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we report an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a-/- mice exhibit altered adrenal gland morphology, as reflected by a diminished X-zone, enlarged medulla, and dysregulated zonation of the glomerulosa as well as increased aldosterone levels and aldosterone target gene expression and reduced plasma potassium levels. Genes involved in catecholamine biosynthesis and cAMP signaling are upregulated in the adrenal glands of Siah1a-/- mice, while genes related to retinoic acid signaling and cholesterol biosynthesis are downregulated. Loss of Siah1 leads to increased expression of the Siah1 substrate PIAS1, an E3 SUMO protein ligase implicated in the suppression of LXR, a key regulator of cholesterol levels in the adrenal gland. In addition, SIAH1 sequence variants were identified in patients with PA; such variants impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression. These data identify a role for the Siah1-PIAS1 axis in adrenal gland organization and function and point to possible therapeutic targets for hyperaldosteronism.
| S-EPMC5752272 | biostudies-literature
Project description:The effects of retinoids on adrenal aldosterone synthase gene (CYP11B2) expression and aldosterone secretion are still unknown. We therefore examined the effects of nuclear retinoid X receptor (RXR) pan-agonist PA024 on CYP11B2 expression, aldosterone secretion and blood pressure, to elucidate its potential as a novel anti-hypertensive drug. We demonstrated that PA024 significantly suppressed angiotensin II (Ang II)-induced CYP11B2 mRNA expression, promoter activity and aldosterone secretion in human adrenocortical H295R cells. Human CYP11B2 promoter functional analyses using its deletion and point mutants indicated that the suppression of CYP11B2 promoter activity by PA024 was in the region from -1521 (full length) to -106 including the NBRE-1 and the Ad5 elements, and the Ad5 element may be mainly involved in the PA024-mediated suppression. PA024 also significantly suppressed the Ang II-induced mRNA expression of transcription factors NURR1 and NGFIB that bind to and activate the Ad5 element. NURR1 overexpression demonstrated that the decrease of NURR1 expression may contribute to the PA024-mediated suppression of CYP11B2 transcription. PA024 also suppressed the Ang II-induced mRNA expression of StAR, HSD3β2 and CYP21A2, a steroidogenic enzyme group involved in aldosterone biosynthesis. Additionally, the PA024-mediated CYP11B2 transcription suppression was shown to be exerted via RXRα. Moreover, the combination of PPARγ agonist pioglitazone and PA024 caused synergistic suppressive effects on CYP11B2 mRNA expression. Finally, PA024 treatment significantly lowered both the systolic and diastolic blood pressure in Tsukuba hypertensive mice (hRN8-12 x hAG2-5). Thus, RXR pan-agonist PA024 may be a candidate anti-hypertensive drugs that acts via the suppression of aldosterone synthesis and secretion.
| S-EPMC5553648 | biostudies-other
Project description:The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by data from genome-wide association studies that consistently link the CYP17A1 locus to blood pressure. In this review article, we describe common polymorphisms at three steroidogenic loci (CYP11B2, CYP11B1 and CYP17A1) that alter gene transcription efficiency and levels of key steroids, including aldosterone. However, the mechanism by which this occurs remains unclear. While the renin angiotensin system is rightly regarded as the major driver of aldosterone secretion, there is increasing evidence that the contribution of corticotropin (ACTH) is also significant. In light of this, we propose that the differential response of variant CYP11B2, CYP11B1 and CYP17A1 genes to ACTH is an important determinant of blood pressure, tending to predispose individuals with an unfavourable genotype to hypertension.
| S-EPMC5372595 | biostudies-literature
Project description:Prolonged exposure to chronic sleep restriction (CSR) and shiftwork are both associated with incident hypertension and cardiovascular disease. We hypothesized that the combination of CSR and shiftwork's rotating sleep schedule (causing recurrent circadian disruption, RCD) would increase blood pressure, renal sodium retention, potassium excretion, and aldosterone excretion. Seventeen healthy participants were studied during a 32-day inpatient protocol that included 20-h "days" with associated scheduled sleep/wake and eating behaviors. Participants were randomly assigned to restricted (1:3.3 sleep:wake, CSR group) or standard (1:2 sleep:wake, Control group) ratios of sleep:wake duration. Systolic blood pressure during circadian misalignment was ∼6% higher in CSR conditions. Renal sodium and potassium excretion showed robust circadian patterns; potassium excretion also displayed some influence of the scheduled behaviors (sleep/wake, fasting during sleep so made parallel fasting/feeding). In contrast, the timing of renal aldosterone excretion was affected predominately by scheduled behaviors. Per 20-h "day," total sodium excretion increased, and total potassium excretion decreased during RCD without a change in total aldosterone excretion. Lastly, a reduced total renal sodium excretion was found despite constant oral sodium consumption and total aldosterone excretion, suggesting a positive total body sodium balance independent of aldosterone excretion. These findings may provide mechanistic insight into the observed adverse cardiovascular and renal effects of shiftwork.
| S-EPMC9305384 | biostudies-literature
Project description:ObjectivesThis study postulated that antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibition may mitigate vascular endothelial growth factor inhibitor (VEGFi)-mediated increases in blood pressure more effectively than other antihypertensive medications in patients receiving VEGFi therapy.BackgroundVEGFi therapy is commonly used in the treatment of cancer. One common side effect of VEGFi therapy is elevated blood pressure. Evidence suggests that the RAAS may be involved in VEGFi-mediated increases in blood pressure.MethodsThis retrospective cohort analysis was performed using a de-identified version of the electronic health record at Vanderbilt University Medical Center in Nashville, Tennessee. Subjects with cancer who were exposed to VEGFi therapy were identified, and blood pressure and medication data were extracted. Changes in mean systolic and diastolic blood pressure in response to VEGFi therapy in patients receiving RAAS inhibitor (RAASi) therapy before VEGFi initiation were compared with changes in mean systolic and diastolic blood pressure in patients not receiving RAASi therapy before VEGFi initiation.ResultsMean systolic and diastolic blood pressure rose in both groups after VEGFi use; however, patients who had RAASi therapy before VEGFi initiation had a significantly lower increase in systolic blood pressure as compared with patients with no RAASi therapy (2.46 mm Hg [95% confidence interval: 0.7 to 4.2] compared with 4.56 mm Hg [95% confidence interval: 3.5 to 5.6], respectively; p = 0.034).ConclusionsIn a real-world clinical population, RAASi therapy before VEGFi initiation may ameliorate VEGFi-mediated increases in blood pressure. Randomized clinical trials are needed to further our understanding of the role of RAASi therapy in VEGFi-mediated increases in blood pressure. (J Am Coll Cardiol CardioOnc 2019;1:14-23).
| S-EPMC7513950 | biostudies-literature