CD4+ Tregs drive post-ischemic sprouting angiogenesis via endothelial YY1/MAML1 reactivation [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE331194 | GEO | 2026/05/18
REPOSITORIES: GEO
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Project description:Microvascular complications of diabetes are chronic diseases of small vessels. We previously found that CD4+ regulatory T-cells (Tregs) are markedly reduced in type 2 diabetes (T2D) after ischemic injury in both mice and humans, and that Treg deficiency in immunodeficient mice impairs vascular regeneration. However, the mechanisms by which Tregs protect against diabetic vascular disease remain unclear. Here, we demonstrate that endothelial cells (ECs) upregulate the transcription factor YY1 during post-ischemic vascular regeneration, but this response is blunted in diabetic ECs. Endothelial-specific deletion of YY1 leads to defective vascular regeneration following ischemia. Mechanistically, YY1 binds to the MAML1 promoter at regions enriched for H3K4me3 and H3K27ac. YY1 activates MAML1 transcription, likely by recruiting H3K4me3 writers (SETD1A, MLL1, MLL2) and their scaffold WDR5 within the COMPASS complex, together with the H3K27ac writer p300. Functionally, Tregs enhance vascular regeneration through paracrine signaling even in T2D mice. Adoptive Treg transfer restores regenerative capacity by reactivating the endothelial YY1/MAML1 axis. These findings identify a Treg-YY1-MAML1 pathway as a key regulator of endothelial function and vascular repair, offering mechanistic insight into how Tregs promote tissue regeneration in diabetes-associated microvascular dysfunction.
2026-05-18 | GSE331193 | GEO
Project description:BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, non-invasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without (testing set: AUC = 0.85, 95%CI, 0.73-0.96), outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84, 95%CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, non-invasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.
2020-01-31 | GSE125929 | GEO
Project description:The central nervous system (CNS) hypothalamus controls systemic metabolism. Inflammatory CNS processes evolving upon exposure to calorie-rich diet are thought to promote impaired metabolic CNS control, thereby triggering obesity and Type-2 diabetes (T2D). However, immune cells relevant for maintaining hypothalamic integrity remain incompletely understood. Here, we identify hypothalamic CD4+Foxp3+regulatory T(Treg) cells which control local tissue-inflammation. Specifically, upon exposure to a calorie-rich diet, a significant decline in hypothalamus-residing Foxp3+Tregs occurred and was accompanied by increased immune activation of CD4+T cells, infiltrating macrophages and microglia. Microglial proteomes of mice exposed to the hypercaloric challenge confirmed characteristics of immune activation; specifically, mRNA expression profiling of hypothalamic CD4+T cells indicated a Th1-mediated inflammatory state evidenced by high levels of Tbx21, Cxcr3, Cd226 and reduced expression of Ccr7 and S1P1 receptors relevant for recruitment to and retention at inflammatory sites. Using Treg depletion and transfer experiments in vivo, we found that Foxp3+Tregs critically limit hypothalamic immune activation induced by hyper-caloric challenge. Our findings open new avenues in the design of tailored concepts to improve immunometabolic health in obesity and T2D.
2025-01-20 | PXD004498 | Pride
Project description:Background: Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) involving adverse endothelial and smooth muscle dysfunction, vascular remodeling, and alterations in mechanics, which culminate in impaired coronary blood flow. Recent data suggest that vascular layer-specific mechanisms, influenced by the surrounding myocardium, contribute to CMD. To investigate transcriptional differences potentially contributing to CMD, we used spatial and single cell transcriptomic profiling of the coronary microcirculation and surrounding myocardium across distinct heart subregions to identify new pathways to target. Methods: We combined single cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Results: Single cell RNA profiling and spatial transcriptomics revealed upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. Using spatial transcriptomics, we also examined gene expression in coronary microvessel-enriched areas across different heart subregions. Interestingly, the most pronounced transcriptional differences between T2D and control coronary microvessels were observed in the left ventricular anterior wall, where inflammatory response pathways were downregulated in T2D mice. Genes associated with oxidative phosphorylation and fatty acid oxidation were significantly upregulated in T2D coronary microvessels within the left ventricular anterior wall.Conclusions: These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D – characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization – contributes to oxidative stress and lipotoxicity, key drivers of heart failure. Furthermore, these data reveal previously unrecognized transcriptomic differences in coronary microvessels across spatially-distinct regions of the T2D heart, suggesting transcriptional heterogeneity in this critical vascular bed.
2025-12-10 | GSE290094 | GEO
Project description:Background: Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) involving adverse endothelial and smooth muscle dysfunction, vascular remodeling, and alterations in mechanics, which culminate in impaired coronary blood flow. Recent data suggest that vascular layer-specific mechanisms, influenced by the surrounding myocardium, contribute to CMD. To investigate transcriptional differences potentially contributing to CMD, we used spatial and single cell transcriptomic profiling of the coronary microcirculation and surrounding myocardium across distinct heart subregions to identify new pathways to target. Methods: We combined single cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Results: Single cell RNA profiling and spatial transcriptomics revealed upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. Using spatial transcriptomics, we also examined gene expression in coronary microvessel-enriched areas across different heart subregions. Interestingly, the most pronounced transcriptional differences between T2D and control coronary microvessels were observed in the left ventricular anterior wall, where inflammatory response pathways were downregulated in T2D mice. Genes associated with oxidative phosphorylation and fatty acid oxidation were significantly upregulated in T2D coronary microvessels within the left ventricular anterior wall.Conclusions: These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D – characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization – contributes to oxidative stress and lipotoxicity, key drivers of heart failure. Furthermore, these data reveal previously unrecognized transcriptomic differences in coronary microvessels across spatially-distinct regions of the T2D heart, suggesting transcriptional heterogeneity in this critical vascular bed.
2025-12-10 | GSE290095 | GEO
Project description:Type II diabetes mellitus (T2D) is a chronic metabolic disease, and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males exposing large knowledge gaps in females. Therefore, the aim of this study was to evaluate the consequence of T2D on cognitive function, and decipher underlying molecular transcriptomic mechanisms of endothelial cells in an important memory center, the hippocampus, in female diabetic mice. Adult female db/db and control wild type mice (n=10/group) were studied at age 18 weeks after which cognitive performance was assessed, metabolic parameters measured, and the hippocampus isolated for single nuclei RNA sequencing. db/db female mice exhibit characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared to female WT mice. Female db/db mice presented cognitive decline compared to wild type mice. snRNAseq showed that T2D induced significant change in the global transcriptome profile of hippocampal endothelial cells by modulating expression of not only protein coding genes but also lncRNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization and cell adhesion, suggesting that diabetes increases endothelial cell permeability and therefore blood-brain permeability (BBB). Observed genomic changes also correlated with clinical Alzheimer’s and vascular dementia. In conclusion, T2D, by multiomic transcriptional and post transcriptional regulation, modulates the expression of genes in brain endothelial cells, resulting in endothelial cell dysfunction predictive of increased BBB permeability, and negatively impacts cognitive function.
2025-03-19 | GSE241693 | GEO
Project description:Chen2006 - Nitric Oxide Release from
Endothelial Cells
This model is described in the article:
Theoretical analysis of
biochemical pathways of nitric oxide release from vascular
endothelial cells.
Chen K, Popel AS.
Free Radic. Biol. Med. 2006 Aug; 41(4):
668-680
Abstract:
Vascular endothelium expressing endothelial nitric oxide
synthase (eNOS) produces nitric oxide (NO), which has a number
of important physiological functions in the microvasculature.
The rate of NO production by the endothelium is a critical
determinant of NO distribution in the vascular wall. We have
analyzed the biochemical pathways of NO synthesis and
formulated a model to estimate NO production by the
microvascular endothelium under physiological conditions. The
model quantifies the NO produced by eNOS based on the kinetics
of NO synthesis and the availability of eNOS and its
intracellular substrates. The predicted NO production from
microvessels was in the range of 0.005-0.1 microM/s. This range
of predicted values is in agreement with some experimental
values but is much lower than other rates previously measured
or estimated from experimental data with the help of
mathematical modeling. Paradoxical discrepancies between the
model predictions and previously reported results based on
experimental measurements of NO concentration in the vicinity
of the arteriolar wall suggest that NO can also be released
through eNOS-independent mechanisms, such as catalysis by
neuronal NOS (nNOS). We also used our model to test the
sensitivity of NO production to substrate availability, eNOS
concentration, and potential rate-limiting factors. The results
indicated that the predicted low level of NO production can be
attributed primarily to a low expression of eNOS in the
microvascular endothelial cells.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000676.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000676 | BioModels
Project description:Analysis of ex vivo isolated lymphatic endothelial cells from the dermis of patients to define type 2 diabetes-induced changes. Results preveal aberrant dermal lymphangiogenesis and provide insight into its role in the pathogenesis of persistent skin inflammation in type 2 diabetes. The ex vivo dLEC transcriptome reveals a dramatic influence of the T2D environment on multiple molecular and cellular processes, mirroring the phenotypic changes seen in T2D affected skin. The positively and negatively correlated dLEC transcripts directly cohere to prolonged inflammatory periods and reduced infectious resistance of patients´ skin. Further, lymphatic vessels might be involved in tissue remodeling processes during T2D induced skin alterations associated with impaired wound healing and altered dermal architecture. Hence, dermal lymphatic vessels might be directly associated with T2D disease promotion. Global gene expression profile of normal dermal lymphatic endothelial cells (ndLECs) compared to dermal lymphatic endothelial cells derived from type 2 diabetic patients (dLECs).Quadruplicate biological samples were analyzed from human lymphatic endothelial cells (4 x diabetic; 4 x non-diabetic). subsets: 1 disease state set (dLECs), 1 control set (ndLECs)
2012-06-01 | E-GEOD-38396 | biostudies-arrayexpress
Project description:Diabetes mellitus [DM], with its burden of premature morbidity and mortality, represents one of the major threats to human health in the 21st century (Zimmet 2001). Accelerated atherosclerosis affecting arteries that supply the heart, brain and lower extremities is responsible for an increased risk of acute ischemic events. DM is also associated with microvascular disease, which is a leading cause of blindness, renal failure and debilitating neuropathies. Endothelial dysfunction, increased vascular permeability and microvascular cell loss by apoptosis are all hallmarks of diabetic microangiopathy. Diabetic patients not only incur cardiovascular complications more frequently, but also experience worse outcomes due to attenuation of vascular repair mechanisms. This impairment includes quantitative and qualitative abnormalities of bone marrow [BM]-derived progenitor cells (Emanueli 2002&2004; Loomans 2004; Krankel 2005; Fadini 2006). The mechanisms underlying BM dysfunction remain however enigmatic, especially when considering the privileged location that protects stem cells [SC] and progenitor cells [PC] of the marrow from external insults (Kopp 2008 and Kiel 2008). BM endothelial cells [EC] are instead an obvious target of DM, because they are directly exposed to blood glucose and incapable to regulate glucose influx. Strangely enough, little is known about the impact of diabetes on BM microvasculature. We hypothesize that damage induced by DM might start at the microvascular level, in a similar fashion to microangiopathy, which occurs in kidney, retina, heart and brain. We also propose that enduring microvascular cell loss might result in marrow hypo-perfusion and destabilization of SC homeostasis. In order to test this hypothesis, we studied streptozotocin-induced (STZ) type-1 DM and age-matched non-DM mice (n=6 to 10 per group in each experiment). Histological examination of femurs, collected from STZ-mice at 28-30 weeks from induction of DM or controls, showed remarkable differences in bone density and marrow composition. Bone marrow cells from healthy and diabetic animals were next selected for endothelial progenitors and cultured for 10 days under endothelial cell growth conditions. Next RNA was isolated and analysed by Illumina Sentrix Beadarrays.
2010-07-01 | E-GEOD-14035 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are critically involved in neovascularization, an important compensatory mechanism in peripheral artery disease (PAD). The contribution of G protein coupled receptor 174 (GPR174), which is a regulator of Treg function and development, in neovascularization remains elusive. Here, we reveal that genetic deletion of GPR174 in Tregs potentiated blood flow recovery in mice after hindlimb ischemia (HLI). GPR174 deficiency upregulates amphiregulin (AREG) expression in Tregs, thereby enhancing endothelial cell functions and reducing pro-inflammatory macrophage polarization and endothelial cell apoptosis. Mechanically, GPR174 regulates AREG expression by inhibiting the nuclear accumulation of early growth response protein 1 (EGR1) via Gαs/cAMP/PKA signal pathway activation. Collectively, these findings demonstrate that GPR174 negatively regulates angiogenesis and vascular remodeling in response to ischemic injury and that GPR174 may be a potential molecular target for therapeutic interventions of ischemic vascular diseases.
2022-10-03 | GSE214684 | GEO