Vascular Regulation Research Articles

ANK Deficiency-Mediated Cytosolic Citrate Accumulation Promotes Aortic Aneurysm.

Disturbed metabolism and transport of citrate play significant roles in various pathologies. However, vascular citrate regulation and its potential role in aortic aneurysm (AA) development remain poorly understood. Untargeted metabolomics by mass spectrometry was applied to identify upregulated metabolites of the tricarboxylic acid cycle in AA tissues of mice. To investigate the role of citrate and its transporter ANK (progressive ankylosis protein) in AA development, vascular smooth muscle cell (VSMC)-specific Ank-knockout mice were used in both Ang II (angiotensin II)- and CaPO4-induced AA models. Citrate was abnormally increased in both human and murine aneurysmal tissues, which was associated with downregulation of ANK, a citrate membrane transporter, in VSMCs. The knockout of Ank in VSMCs promoted AA formation in both Ang II- and CaPO4-induced AA models, while its overexpression inhibited the development of aneurysms. Mechanistically, ANK deficiency in VSMCs caused abnormal cytosolic accumulation of citrate, which was cleaved into acetyl coenzyme A and thus intensified histone acetylation at H3K23, H3K27, and H4K5. Cleavage under target and tagmentation analysis further identified that ANK deficiency-induced histone acetylation activated the transcription of inflammatory genes in VSMCs and thus promoted a citrate-related proinflammatory VSMC phenotype during aneurysm diseases. Accordingly, suppressing citrate cleavage to acetyl coenzyme A downregulated inflammatory gene expression in VSMCs and restricted ANK deficiency-aggravated AA formation. Our studies define the pathogenic role of ANK deficiency-induced cytosolic citrate accumulation in AA pathogenesis and an undescribed citrate-related proinflammatory VSMC phenotype. Targeting ANK-mediated citrate transport may emerge as a novel diagnostic and therapeutic strategy in AA.

Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats.

In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT1D/1A and 5-HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved. Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1-5 Hz) or i.v. noradrenaline (0.01-0.5 μg·kg-1). 5-HT-related drug effects on adrenergic system were determined. Age-matched male rats were used as control. Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT1/5/7) and L-694,247 (5-HT1D), whereas the selective 5-HT2A/2B/2C (α-methyl-5-HT) and 5-HT3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT1A/1B/1F, 5-HT2B/2C, 5-HT4, 5-HT5A or 5-HT7) modified these vasoconstrictions. Only 1-PBG (5-HT3) modified the vasoconstrictions induced by exogenous noradrenaline. In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT1D receptor activation, whereas pre and/or postjunctional 5-HT3 and prejunctional 5-HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions.

Circulating thrombospondin 2 as a predictor of hepatocellular carcinoma in hepatitis B patients undergoing nucleos(t)ide analog therapy

Thrombospondin 2 (TSP2) plays a vital role in collagen/fibrin formation, bone growth, vascular density regulation, hemostasis, and cell adhesion. Close associations of serum TSP2 with histological severity in non-alcoholic fatty liver disease and chronic hepatitis C were reported. The present study investigated the significance of circulating TSP2 in chronic hepatitis B patients. Eighty-seven biopsy-proven chronic hepatitis B patients were analyzed in cross-sectional Study 1 to search for correlations between serum TSP2 levels prior to liver biopsy and clinicopathological parameters. In longitudinal Study 2, 51 chronic hepatitis B patients with long-term follow-up (mean: 7.5 years) were examined for changes in serum TSP2 levels during nucleos(t)ide analog (NA) therapy along with trends in hepatocarciongenesis. In Study 1, serum TSP2 levels were not significantly associated with portal inflammation or fibrosis. Study 2 revealed that serum TSP2 was significantly decreased after 48 weeks of NA therapy (P < 0.001). Notably, TSP2 levels at 48 weeks of NA administration (TSP2-48W) were significantly higher in the hepatocellular carcinoma (HCC) (+) group than in the HCC (−) group (P = 0.043). Kaplan–Meier analysis showed that higher TSP2-48W (≥ 24 ng/mL) was associated with future HCC development (P = 0.030). Serum TSP2 levels may be a potential predictor of HCC development in hepatitis B patients receiving NA therapy. Longitudinal prospective studies are necessary to validate our findings.

Therapeutic mechanism and key active ingredients of Yinxing Mihuan Oral Solution in coronary heart disease comorbidity with anxiety: A network pharmacology and molecular docking approach.

Yinxing Mihuan Oral Solution (YMOS) is a Chinese patent medicine for treating coronary heart disease combined anxiety (CHDCA), but the molecular mechanism of its treatment is still unclear. This article aims to understand the molecular mechanism, optimize clinical drug use, and guide new drug development. Using the Swiss Target Prediction database, we obtained the main chemical composition of YMOS. Then we used network pharmacology to identify their potential targets. Network construction, coupled with protein-protein interaction and enrichment analysis was used to identify representative components and core targets. Finally, molecular docking simulation was conducted to further refine the drug-target interaction. Forty-two active chemicals were found in YMOS and 91 target genes related to CHDCA. The treatment effect was found to be associated with 1908 biological processes and 160 pathways, as revealed by the outcomes of the enrichment analysis. The potential therapeutic mechanisms of the drug are closely related to its antioxidant, anti-inflammatory, and vascular function regulation pathways, and the main core targets include albumin, tumor necrosis factor, TP53, AKT serine/threonine kinase 1, interleukin 1 beta, and vascular endothelial growth factor A. The potential molecular mechanisms of YMOS in CHDCA treatment were identified using network pharmacology and molecular docking approaches. The results reveal the systemic biological implications of YMOS. This study has systematically uncovered the molecular mechanism of YMOS for the first time, offering fresh insights for evidence-based clinical applications.

Autonomic control of the pulmonary circulation: Implications for pulmonary hypertension.

The autonomic regulation of the pulmonary vasculature has been under-appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension.

Human sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y bioavailability.

What is the purpose of sympathetic neuronal action potential (AP) discharge and recruitment patterns for human vascular regulation? This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. We used microneurography to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to detect sympathetic APs during a baseline condition and intravenous dexmedetomidine infusion (α2-adrenergic agonist, 10 min loading infusion of 0.225 µg kg-1; maintenance infusion of 0.1-0.5 µg kg h-1) in six healthy individuals (5 females, 27 ± 6 years). Arterial blood samples provided NPY (enzyme-linked immunosorbent assay) and norepinephrine (Liquid Chromatography Tandem Mass Spectrometry) levels during baseline and the dexmedetomidine maintenance infusion. Linear mixed model regressions assessed the relationships between AP discharge, recruitment, and neurotransmitter levels. Across baseline and the dexmedetomidine condition, NPY levels were positively related to mean arterial pressure (β = 1.63 [0.34], P = 0.002), total AP clusters (β = 0.90 [0.22], P = 0.005), and AP frequency (β = 0.11 [0.03], P = 0.003). Norepinephrine levels were not related to mean arterial pressure (β = 0.03 [0.02], P = 0.133) but were positively related to total AP clusters (β = 19.50 [7.07], P = 0.030) and AP frequency (β = 2.66 [0.81], P = 0.014). These data suggest that sympathetic neuronal discharge and recruitment patterns regulate NPY and norepinephrine bioavailability in healthy adults. As such, sympathetic neuronal firing strategies are important for human vascular regulation.

APOE4 carriers display loss of anticipatory cerebral vascular regulation over AD progression.

Maintenance of cerebral blood flow during orthostasis is impaired with aging and associated with cognitive decline, but the effect of Apolipoprotein 4-allele (APOE4) is unknown. Older adults (n=108) (APOE4 carriers, n=47; noncarriers, n=61) diagnosed as cognitively-normal (NC), MCI, or AD participated. Middle cerebral artery blood velocity (MCAv), assessed using Transcranial Doppler ultrasound, and beat-to-beat mean arterial blood pressure (MAP) were continuously recorded during a sit-to-stand transition. Anticipatory and orthostatic-induced MCAv and MAP responses were compared between genotypes and across disease progression. Cognitively-normal APOE4 carriers showed greater anticipatory MCAv increase, greater MCAv decrease with orthostasis, and shorter latency of peripheral MAP responses to orthostasis compared to noncarriers. MCAv and MAP responses were delayed and attenuated across the APOE4 disease progression, with no differences between genotypes in MCI and AD. APOE4 carriers and noncarriers present with distinct phenotypes of cerebral vascular dysfunction during hemodynamic orthostatic challenge. Unique cerebral and peripheral vascular compensation observed in APOE4 carriers may be lost as AD progresses.

8532 Circulating Neprilysin in Pregnancy

Abstract Disclosure: A. Kulovic-Sissawo: None. E. Weiss: None. E. Jantscher-Krenn: None. U. Hiden: None. Background: In the complex nature of pregnancy, the female organism undergoes pivotal vascular and metabolic changes orchestrated by a tightly regulated interplay of bioactive regulatory molecules. The neutral endopeptidase, neprilysin, exists both in a membrane-bound and a soluble form (sNEP), of with the latter present in the circulatory system. Neprilysin degrades an exciting range of bioactive peptides involved in glycemic control (insulin B chain, GLP-1) and vascular tone regulation (angiotensin I and II, bradykinin, ANP, BNP), and both of them are altered in pregnancy. Objective: Due to the substrate-specificity of neprilysin and its multifaceted role we hypothesize that neprilysin may be involved in metabolic and vascular adaptions during pregnancy. However, the link between sNEP and maternal metabolism in pregnancy has not yet been investigated. Methodology: Serum sNEP concentration (n=102), longitudinally collected from metabolically healthy women (trial number NTC05496712), was measured at three visits throughout gestation (gestational age: 12.5±0.7; 20±0.8; 33±1.6 weeks) and post-partum (2±1.2 days after delivery) using commercially available sandwich ELISA. In addition, sNEP levels in pregnancy were compared to a cohort of non-pregnant women within reproductive age (n=50). Clinical and anthropometric measurements were determined and the association of sNEP and metabolic characteristics elucidated. Results: Circulating sNEP levels were non-normally distributed (median ± IQR: 2334±232624 pg/ml, n=82, gestational age 12.5±0.7 weeks) and showed high biological variability, with individual levels remaining constant over gestation. After delivery, however, sNEP concentration decreased (median± IQR: 1968±171060 pg/ml n=82, p=0.0001). sNEP showed a positive correlation with systolic blood pressure (Spearman, n=56, r=0.321, p=0.02) at early stages of pregnancy and non-fasting GLP-1 (Spearman, n=98, r=0.309, p=0.002) throughout gestation, but not with blood glucose, insulin resistance or BMI. In the non-pregnant state sNEP concentration (median±IQR: 4322±392152 pg/ml, n=38) positively correlated with body fat percentage (Pearson, n=38, r=0.405, p=0.01), fasting glucose (Pearson, n=43, r=0.301, p=0.05) and body mass index (Spearman, n=38, r=0.369, p=0.02) but did not correlate with systolic blood pressure (Pearson, n=36, r=-0.120, p=0.48). Conclusion: For the first time, the link between sNEP, metabolism and blood pressure during uncomplicated pregnancy was investigated. The decrease in post-partum circulating sNEP as compared to levels throughout pregnancy suggests a particular way of sNEP regulation and release during gestation. Our data indicate that in both, pregnant and non-pregnant state, sNEP may be involved in metabolic and cardiovascular regulation, with circulating sNEP levels showing massive individual differences. Presentation: 6/3/2024

From Microbes to Myocardium: A Comprehensive Review of the Impact of the Gut-Brain Axis on Cardiovascular Disease.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide despite advances in medical research and therapeutics. Emerging evidence suggests a significant role of the gut-brain axis, a complex communication network involving the gut microbiota, central nervous system, and cardiovascular system, in modulating cardiovascular health. The gut microbiota influences systemic inflammation, neurohumoral pathways, and metabolic processes, which are critical in the pathogenesis of CVD. Dysbiosis, or an imbalance in the gut microbiota, has been implicated in various cardiovascular conditions, including hypertension, atherosclerosis, and heart failure. This comprehensive review aims to elucidate the intricate relationship between the gut microbiome, brain, and cardiovascular system, highlighting the mechanisms by which gut-derived signals affect cardiovascular function. Key microbial metabolites, such as short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO), and their impact on vascular health and blood pressure regulation are discussed. Furthermore, the review explores potential therapeutic strategies targeting the gut-brain axis, including probiotics, prebiotics, dietary modifications, and pharmacological interventions, to improve cardiovascular outcomes. Despite promising findings, the field faces challenges such as individual variability in microbiome composition, complexities in gut-brain interactions, and the need for robust clinical trials to establish causality. Addressing these challenges through interdisciplinary research could pave the way for innovative, personalized therapeutic approaches. This review provides a comprehensive understanding of the gut-brain-cardiovascular axis, underscoring its potential as a novel target for preventing and treating CVD.

Regulation of Skeletal Muscle Resistance Arteriolar Tone: Temporal Variability in Vascular Responses

Introduction: A full understanding of the integration of the mechanisms of vascular tone regulation requires an interrogation of the temporal behavior of arterioles across vasoactive challenges. Building on previous work, the purpose of the present study was to start to interrogate the temporal nature of arteriolar tone regulation with physiological stimuli. Methods: We determined the response rate of ex vivo proximal and in situ distal resistance arterioles when challenged by one-, two-, and three-parameter combinations of five major physiological stimuli (norepinephrine, intravascular pressure, oxygen, adenosine [metabolism], and intralumenal flow). Predictive machine learning models determined which factors were most influential in controlling the rate of arteriolar responses. Results: Results indicate that vascular response rate is dependent on the intensity of the stimulus used and can be severely hindered by altered environments, caused by application of secondary or tertiary stimuli. Advanced analytics suggest that adrenergic influences were dominant in predicting proximal arteriolar response rate compared to metabolic influences in distal arterioles. Conclusion: These data suggest that the vascular response rate to physiologic stimuli can be strongly influenced by the local environment. Translating how these effects impact vascular networks is imperative for understanding how the microcirculation appropriately perfuses tissue across conditions.

Exploring the role of endoplasmic reticulum stress in recurrent spontaneous abortion: Identification of diagnostic biomarkers and immune cell interactions

Dysregulated endoplasmic reticulum stress (ERS) is associated with recurrent spontaneous abortion (RSA) and is involved in the mechanisms that govern immune balance and vascular regulation at the maternal-fetal interface. The molecular intricacies of these mechanisms remain elusive. This study employed microarray and bioinformatics techniques to examine genetic abnormalities in endometrial tissues from RSA patients, with the objective of identifying potential ERS-related biomarkers. By integrating two publicly available microarray datasets, consisting of 88 RSA and 42 control samples, we conducted an extensive analysis, including differential expression, functional annotation, molecular interactions, and immune cell infiltration. Analysis of immune cell characteristics suggests an inflammatory immune imbalance as a potential contributor to RSA progression. Both innate and adaptive immunity were found to play roles in RSA development, with M1 macrophages constituting a significant proportion of immune infiltration. We identified five key ERS-associated genes (TMEM33, QRICH1, MBTPS2, ERN1, and BAK1) linked to immune-related mechanisms, with RT-qPCR results aligning with bioinformatics findings. Our research findings offer a fresh and comprehensive perspective on the ERS-related genes' pathways and interaction networks, offering significant insights for the advancement of innovative therapy techniques for RSA.

Relationship of Dickkopf-1 With Atherosclerosis and Arterial Stiffness in Renal Transplant Recipients

IntroductionDickkopf wingless (Wnt) signaling pathway inhibitor-1 (DKK-1) is a potent antagonist of the WNT canonical signaling pathway. DKK-1 is a substance that exerts anabolic effects on bone and is also involved in vascular cell regulation. The study aimed to determine the relationship of DKK-1 with atherosclerosis as determined by carotid artery intima-media thickness (CA-IMT) and arterial stiffness (AS) as determined by brachial-ankle pulse wave velocity (baPWV) in renal transplant recipients (RTRs). MethodsA total of 62 (62%) male and 38 (438%) female RTRs with a mean age of 44.22 ± 10.88 years were included in the study. RTRs were compared with 65 healthy individuals. CA-IMT measurement with ultrasonography was used as a marker of atherosclerosis. The presence of AS was detected with the baPWV device. ResultsCreatinine, CA-IMT, and baPWV were higher in the RTRs compared to the healthy subjects. No difference was determined between the two groups regarding log10 DKK-1. No difference was noted in the levels of CA-IMT and baPWV in patients with log10 DKK-1 > 3.83 pg/mL compared to patients with ≤3.83 pg/mL. Correlation and multivariate analyses showed no correlation between log10 DKK-1 and CA-IMT and baPWV. DiscussionIn RTRs, an increased development of atherosclerosis and AS was observed compared to healthy individuals. There was no difference in DKK-1 between the groups based on improved renal function. DKK-1 was not correlated with atherosclerosis and AS.

Integrated transcriptomics and lipidomics reveals protective effect in vascular endothelial barrier of a polysaccharide from Typhae Pollen

Endothelial cell dysfunction caused by inflammation and even vascular leakage are important manifestations of blood stasis syndrome (BSS). Reversible regulation of vascular integrity to cure BSS has attracted considerable interest. Herein, a novel acidic polysaccharide (TPP-4) was purified and characterized from Typhae Pollen, a typical traditional Chinese medicine for treating BSS, especially for bleeding caused by blood stasis. A series of structural characterization methods, including spectroscopic methods (FT-IR and UV), chromatographic methods (HPGPC, HPAEC-PDA and GC–MS) and NMR, have been used to reveal the fine structure of TPP-4. TPP-4 was a homogeneous heteropolysaccharide comprised with RG-I backbone. TPP-4 showed fantastic activities in vascular integrity regulation both in vitro (HUVECs) and in vivo (zebrafish). Transcriptomics revealed that SOX7 and lipid metabolism were the potential targets. Lipidomics showed that TPP-4 could regulate lipid metabolism disorders caused by vascular inflammation, particularly affecting LPE levels. The above regulatory effects were furtherly demonstrated to be related with VEGFA/PI3K/mTOR signaling pathway through various molecular biological experiments.

TRPV4 Channel in Neurological Disease: from Molecular Mechanisms to Therapeutic Potential.

Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective cation channel with pivotal roles in various physiological processes, including osmosensitivity, mechanosensation, neuronal development, vascular tone regulation, and bone homeostasis in human bodies. Recent studies have made significant progress in understanding the structure and functional role of TRPV4, shedding light on its involvement in pathological processes, particularly in the realm of neurological diseases. Here, we aim to provide a comprehensive exploration of the multifaceted contributions of TRPV4 to neurological diseases, spanning its intricate molecular mechanisms to its potential as a target for therapeutic interventions. We delve into the structural and functional attributes of TRPV4, scrutinize its expression profile, and elucidate the possible mechanisms through which it participates in the pathogenesis of neurological disorders. Furthermore, we discussed recent years' progress in therapeutic strategies aimed at harnessing TRPV4 for the treatment of these diseases. These insights will provide a basis for understanding and designing modality-specific pharmacological agents to treat TRPV4-associated disorders.

The role of microenvironmental factors in the pre-ovulatory oocyte in the pathogenesis of “poor” ovarian response to in vitro fertilization (IVF) programs

Background. The “poor” response to ovarian stimulation during IVF (in vitro fertilization) cycles depends on various factors, including the biochemical composition of the follicle microenvironment. Recent studies have focused on the relationship between vascular tone regulators, angiogenic factors, oxidative stress, and the quality of oocytes. Despite this, there is still no consensus on the exact effect of these factors on folliculogenesis or their role in “poor” responses.Objective. To evaluate the content of biochemical factors and regulators of vascular tone and angiogenesis in follicular fluid in patients with a “poor” ovarian response to stimulation in IVF programs, compared to similar indicators in women with a normal ovarian response.Materials and methods. An open prospective cohort study was conducted, including 56 patients who were part of the IVF program. The criterion for separating the cohort of women was their response to controlled ovarian stimulation during the IVF cycle. Women with a “poor” response (n=32) were placed in the main group, while those with a normal response (n=24) were in the comparison group. Follicular fluid samples from women with a “poor” response were divided into two subgroups based on the presence or absence of an oocyte-cumulus complex in the follicle. The biochemical and soluble regulatory factors in follicular fluid were analyzed in both groups after controlled ovarian stimulation was completed. Statistical analysis of the data was done using methods from variation statistics. A critical level of significance for the differences was set at p ≤0.05.Result. The levels of urea, glucose, high-density lipoprotein, and total antioxidant status (TAOS) in follicular fluid (FF) from patients with a “poor” ovarian response were statistically significantly higher compared to those in the control group. The levels of bilirubin, low-density lipoprotein, and uric acid were also significantly lower in VF from patients in the main group compared to the control group, p&lt;0.05. The indices of vascular endothelial growth factor (VEGF-A) and vascular endothelial growth receptor-2 (VEGFR-2) in FF from women with a “poor” response were significantly lower than those from patients with a normal response, while the levels of endogenous nitric oxide were significantly higher in the former group compared to the latter, p&lt;0.05.Conclusion. The absence of an oocyte-cumulus complex in the pre-ovulatory follicle, which is associated with a “poor” response of the ovary to stimulation, is likely due to a disruption in vascularization processes. This is supported by a decrease in the levels of pro- and anti-angiogenic factors, such as VEGF-A and VEGFR-2.

Cytokine and chemokine receptor profiles in adipose tissue vasculature unravel endothelial cell responses in HIV.

Chronic systemic inflammation significantly increases myocardial infarction risk in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis, contributing to cardiovascular disease. We aimed to characterize endothelial cell (EC) chemokines, cytokine, and chemokine receptors of PLWH, hypothesizing that in our cohort, glucose intolerance contributes to their differential expression implicated in endothelial dysfunction. Using single-cell transcriptomic analysis, we phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in subcutaneous adipose tissue of 59 PLWH with and without glucose intolerance. Our results show that arterial and capillary ECs express significantly higher interferon and tumor necrosis factor (TNF) receptors than venous ECs and VSMCs. Venous ECs exhibited more interleukin (IL)1R1 and ACKR1 receptors, and VSMCs showed significant IL6R expression than arterial and capillary ECs. When stratified by group, arterial ECs from PLWH with glucose intolerance expressed significantly higher IL1R1, IL6R, CXCL12, CCL14, and ICAM2 transcripts than arterial ECs from PLWH without diabetes. Of the different vascular cell types studied, arterial ECs as a proportion of all ECs in adipose tissue were positively correlated with plasma fasting blood glucose. In contrast, venous ECs and VSMCs were positively correlated with plasma IL6. To directly assess the effect of plasma from PLWH on endothelial function, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk RNA sequencing. Plasma from PLWH stimulated ECs with the upregulation of genes that enrich for the oxidative phosphorylation and the TNF-α via NFK-β pathways. In conclusion, ECs in PLWH show heterogeneous cytokine and chemokine receptor expression, and arterial ECs were the most influenced by glucose intolerance. Further research must explicate cytokine and chemokine roles in EC dysfunction and identify biomarkers for disease progression and therapeutic response.

Bioinformatics-based Identification of Ferroptosis-related Genes and their Diagnostic Value in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is considered a risk factor for heart metabolic disorder in future mothers and offspring. Ferroptosis is a new type of programmed cell death, which may participate in the occurrence and development of GDM. This study aims to identify ferroptosis-related genes in GDM by bioinformatics methods and to explore their clinical diagnostic value. The dataset GSE103552 was analyzed using the Gene Expression Omnibus (GEO) database to screen for differentially expressed genes (DEGs) in GDM. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and proteinprotein interaction (PPI) network were performed. Gene sets for ferroptosis were retrieved in MSigDB and GSVA gene set analysis was performed on the database. Finally, logistic regression was performed to differentiate between GDM patients and controls to screen for diagnostic markers. A total of 179 DEGs were identified in the expression profile of GDM. GO and KEGG enrichment analysis revealed significant enrichment in the TGF-β, p53 signaling pathway, platelet activation, glutathione metabolism, sensory perception of taste, and leukocyte and vascular endothelial cell migration regulation. DEGs (n = 107) associated with the ferroptosis gene set were screened by GSVA analysis. The screened DEGs for disease and DEGs for ferroptosis scores were intersected and 35 intersected genes were identified. PPI identified two key genes associated with GDM as CCNB2 and CDK1. Wilcox-test showed low expression of CCNB2 and CDK1 in GDM. The area under the ROC curve (AUC) of the CCNB2 and CDK1 prognostic model was 0.822. The genes associated with ferroptosis in GDM were CCNB2 and CDK1, which can be used as valid indicators for the diagnosis of GDM.

Plasma Proteomics to Identify Drug Targets and Potential Drugs for Retinal Artery Occlusion: An Integrated Analysis in the UK Biobank.

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

Temporal and spatial regulation of biomimetic vascularization in 3D-printed skeletal muscles

Temporal and spatial regulation of biomimetic vascularization in 3D-printed skeletal muscles

Menthol in neck cooling improves subjective comfort but does not affect vascular or temperature regulation

Menthol in neck cooling improves subjective comfort but does not affect vascular or temperature regulation