Vascular Pathway Research Articles

Complex relationships of socioeconomic status with vascular and Alzheimer’s pathways on cognition

IntroductionAD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities [WMH], diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function. MethodsIn this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired). Results(1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition. DiscussionThe utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation.

Serum detection of blood brain barrier injury in subjects with a history of stroke and transient ischemic attack

ObjectiveStroke and transient ischemic attack may have long-term negative effects on the blood-brain barrier (BBB) and promote endothelial inflammation, both of which could increase neurodegeneration and dementia risk beyond the cell death associated with the index event. MethodsSerum from 88 postmortem subjects in the Arizona Study of Aging and Neurodegenerative Disorders were analyzed by sandwich ELISA for specific biomarkers to investigate the effects of cerebrovascular accidents (CVAs) on BBB integrity and endothelial activation. Statistical analyses were performed using the Mann-Whitney U Test, Spearman rank correlation, and linear/logistic regressions adjusted for potential confounders; a P-value < .05 was considered significant for all analyses. ResultsSerum PDGFRẞ, a putative biomarker of BBB injury, was significantly increased in subjects with vs without a history of CVA who had similar cardiovascular risk factors (P < .01). This difference was stable after adjusting for age, hypertension, and other potential confounders in regression analysis (odds ratio, 27.02; 95% confidence interval, 2.61-411.7; P < .01). In addition, PDGFRẞ was positively associated with VCAM-1, a biomarker of endothelial inflammation (ρ = 0.42; P < .01). ConclusionsOur data suggest that patients with stroke or transient ischemic attack have lasting changes in the BBB. Still more, this demonstrates the utility of PDGFRẞ as a serum-based biomarker of BBB physiology, a potentially powerful tool in studying the role of the BBB in various neurodegenerative diseases and COVID infection sequelae. Clinical RelevanceOur data demonstrate the utility of serum PDGFRẞ, a putative biomarker of BBB integrity in the setting of stroke and TIA (CVA). A serum biomarker of BBB integrity could be a useful tool to detect early BBB damage and allow prospective work to study how such damage affects long-term neurodegenerative risk. Since BBB disruption occurs early in ADRD development, it could be monitored to help better understand disease progression and involvement of vascular pathways in ADRD.

Dual-Responsive Reconfigurable Miniature Fiberbots: A Study for Vascular Embolization.

Navigating the intricate and narrow vascular pathways of the body remains a formidable challenge in vascular embolization, often limiting the maneuverability and steerability of traditional catheters. This study, by T.T. Xu and co-workers, introduces dual-responsive reconfigurable miniature fiberbots, which are capable of catheter-assisted deployment, navigation, and embolization in vascular systems. Through meticulous design and magnetic control, this work successfully validates a multistage vascular embolization approach in the renal artery of rabbits invivo. The experiments not only overcome the existing limitations of conventional catheterization techniques but also open new avenues for minimally invasive treatments.

Vascular Access Blood Purification Treatments in Chronic Renal Failure: Impact on Quality of Life

Objective: To observe the effects of blood purification treatment and assess the prognostic impact of different vascular pathways on patients with chronic renal failure (CRF). Methods: A retrospective analysis of clinical data was conducted on 68 CRF cases, categorizing them based on their choice of blood purification vascular access. Group A received an autologous arteriovenous fistula, Group B received an internal jugular vein tunneled polyester sleeve catheter, and Group C received a polytetrafluoroethylene graft vascular fistula. Clinically relevant observation indicators, complication rates, and quality of life scores among the three groups were compared. Results: No significant differences were found between the three groups regarding observed values of clinically relevant indicators and quality of life scores (P &gt; 0.05). When comparing thromboembolism rates Group A had the highest rate, followed by Group C and Group B; for infection rate comparison, Group C had the highest rate, followed by Group B and Group A (P &lt; 0.05). Conclusion: In comparison with the other two vascular access methods, although autologous arteriovenous fistula poses a higher risk of thromboembolism, it exhibits a lower infection rate. Therefore, it is recommended as the preferred vascular access form for blood purification in patients with CRF. If this approach is unavailable, careful consideration should be given. The use of an internal jugular vein with a tunneled polyester sleeve catheter is suggested to better ensure the effectiveness and safety of the patient’s treatment.

Impact of Integrated Vascular Surgery Residency Training Pathway and Professional Development Time on Career Choice and Research Productivity

The limited availability of academic surgery positions has led to increased competition for these jobs. Integrated vascular surgery residency (IVSR) allows for earlier specialization, with some programs providing professional development time (PDT). We hypothesized that IVSR and PDT lead to academic employment and increased research productivity. This is a retrospective study of vascular surgery fellowship (VSF) and IVSR graduates. Training, number of publications, H-index, NIH funding, and employment history were collected using institutional websites, Doximity, Scopus, PubMed, and NIH Research Portfolio Reporting. After a review of the research protocol, the Association of Program Directors in Vascular Surgery (APDVS) provided a list of vascular surgery fellowship (VSF) and IVSR graduates. After review of the research protocol, the Association of Program Directors in Vascular Surgery (APDVS) provided a list of vascular surgery fellowship (VSF) and IVSR graduates. Training, number of publications, H-index, NIH funding, and employment history were collected using institutional websites, Doximity, Scopus, PubMed, and NIH Research Portfolio Reporting. From 2013-2017, comparison of IVSR (n=131) to VSF (n=603) graduates showed that IVSR graduates were more likely to be women (38.17% vs 28.19%; p = 0.024), be MD graduates (99.24% vs 93.37%; p = 0.008), attended programs in the northeast (41.98% vs 27.5%; p < 0.001), have advanced degrees (13.74% vs 6.97%; p = 0.01) and graduate from larger programs (median 15 vs 14 faculty; p = 0.013). There was no significant difference in number of publications per trainee by the end of training (median 4 vs 3; P=0.61) or annual trend in average number of publications. After training, there was no significant difference in the type of practice, academic affiliation, practice region, publication number, H-index, NIH funding, level of academic appointment, or leadership positions. From 2013-2019, a comparison of IVSR graduates with (n=32) and without PDT (n=190) demonstrated that those with PDT were more likely to be women (53.13% vs 34.74%; p = 0.038), have advanced degrees (28.12% vs 8.95%; p = 0.002), be at larger programs (median 14 vs 9 faculty; p < 0.001), train at a top 10 NIH funded program (65.62% vs 21.58%; p < 0.001) and publish more by the end of IVSR (median 9 vs 3; p < 0.001). Graduates with PDT were more likely to have academic employment and affiliation, a higher yearly publication rate, and greater H-index. IVSR and VSF graduates have comparable academic employment and research productivity. However, PDT during IVSR correlates with an eventual academic career and greater research productivity. This study supports the importance of PDT in developing academic vascular surgeons. It remains necessary to continue both IVSR and VSF training paradigms as healthcare needs of the population are met through both academic and non-academic surgeons.

A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection

Aortic dissection (AD) is a fatal cardiovascular disease with limited pharmacotherapies. To discover novel therapeutic targets for AD, the present study was conducted on ascending aorta samples from AD patients versus those from control subjects using proteomic analysis. Integrated proteomic data analysis identified S100 calcium-binding proteins A8 and A9 (S100A8/A9) as new therapeutic targets for AD. As assessed by ELISA, the circulating levels of S100A8/A9 were elevated in AD patients. In addition, we validated the upregulation of S100A8/A9 in a mouse model of AD. In vitro and in vivo studies substantiated that S100A8/A9, as danger-associated molecular pattern molecules, promotes the smooth muscle cells phenotypic switch by inhibiting serum response factor (SRF) activity but elevating NF-κB dependent inflammatory response. Depletion of S100A8/A9 attenuates the occurrence and development of AD. As a proof of concept, we tested the safety and efficacy of pharmacological inhibition of S100A8/A9 by ABR-25757 (paquinimod) in a mouse model of AD. We observed that ABR-25757 ameliorated the incidence of rupture and improved elastin morphology associated with AD. Further single-cell RNA sequencing disclosed that the phenotypic switch of vascular smooth muscle cells (VSMCs) and inflammatory response pathways were responsible for ABR-25757-mediated protection against AD. Thus, this study reveals the regulatory mechanism of S100A8/A9 in AD and offers a potential therapeutic avenue to treat AD by targeting S100A8/A9.

Early Childhood Caries, Masticatory Function, Child Early Cognitive, and Psychomotor Development: A Narrative Review.

Dental caries is known as a global public health issue that has been affecting general health apart from its painful nature. Hence, it is undeniable that caries affecting young children or known as early childhood caries, also have an effect on children's general health. One of the interesting findings about caries is that it can also affect child growth and development, specifically on their cognitive and psychomotor ability. Untreated caries are linked to cognitive development through both neural and vascular pathways, with masticatory function as the key. Meanwhile, its effect on psychomotor development might be related to nutritional intake, which might slightly decline on those with caries. This review is aimed to describe the current findings of caries effect on early child development, from masticatory disturbance to further impacts on cognitive and psychomotor development. The overall conclusion of this review is that untreated severe caries in children are potentially associated negatively with their growth and development.

Proteomic Evolution from Acute to Post-COVID-19 Conditions.

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Vascular dysfunction in behavior‐variant frontotemporal dementia

AbstractBackgroundThe vascular disturbance was recently found in a postmortem study of frontotemporal dementia (FTD), but whether vascular dysfunction exists in the early stage of FTD remains elusive. The study aimed to explore whether there was evidence of vascular dysfunction in FTD and its relationship with central neurodegeneration and the clinical outcome.MethodTwenty patients with behavior frontotemporal dementia (bvFTD) were enrolled and underwent assessment of peripheral plasma vascular markers, positron emission tomography/magnetic resonance imaging, and neuropsychological examinations. Group difference was tested using the student’s t‐test and Mann‐Whitney U test. Partial correlation analysis was implemented using age and sex as covariates to explore the association between peripheral vascular markers, neuroimaging, and clinical measures.ResultAll four factors including matrix metalloproteinases‐1(MMP‐1), matrix metalloproteinases‐3 (MMP‐3), Osteopontin, and pentraxin‐3 are increased in the FTD group. The plasma level of MMP‐1 was negatively correlated with the gray matter metabolism of the prefrontal cortex (r = ‐0.5119, p = 0.0210) and the anterior cingulate cortex (r = ‐0.4685, p = 0.0269). MMP‐3 was negatively correlated with the gray matter metabolism of the anterior temporal cortex (r = ‐0.4650, p = 0.0388). Pentraxin‐3 was negatively correlated with age at sampling (r = ‐0.5024, p = 0.0240) and age at onset (r = ‐0.5693, p = 0.0088). No other significant associations were found in other vascular cytokines and clinical measures.ConclusionThe vascular disturbance was found in patients with bvFTD and associated with the disease‐specific neurodegeneration pattern, indicating vascular dysfunction and perturbance of the BBB participation in the pathogenesis of FTD. The vascular pathway might be a promising target for future potential therapy.

Progress in Research on the Mechanisms and Interventions of Phlebitis from the Perspective of Vascular Endothelial Cell and Signaling Pathway.

Phlebitis is a common complication of intravenous administration and greatly affects clinical outcomes, patient satisfaction, and health-care expenditure. Numerous studies have revealed venous injuries only through visual and histopathological examination. Although sporadic studies have explored the cellular and molecular biological mechanisms of phlebitis and the outcomes of pharmacological interventions, an updated review over the last decade is not available. Progress in research on the mechanisms and interventions of phlebitis was summarized from the perspective of endothelial cells and signaling pathways by retrieving the PubMed, Web of Science Core Collection, MEDLINE, Embase, and CNKI. Phlebitis involves multiple signaling pathways (eg, nuclear factor kappa B, Wnt/β-catenin, focal adhesion kinase/protein kinase B, Toll-like receptor, protein kinase C beta/NADPH oxidase, PI3K/AKT/TNF, and JAK2/STAT3), upregulation of E-selectin, GBP5/NLRP3 inflammasome axis, cell apoptosis, intracellular ROS generation, SOD reduction, stimulation of angiogenesis, and induction of autophagy-associated cell death. Preventive and curative interventions included α-solanine, baicalein, escin, intermedin, Y15, micro-ribonucleic acid-223, sotrastaurin, cimetidine, aescin, resveratrol, α-chaconine, Chahuang ointment, QingLuoTongMai, Mailuo Shutong, and N-acetylcysteine. Laboratory models included vascular endothelial cells, real-time cell-monitoring analysis, network pharmacology analysis and experimental verification in vivo, animal models of phlebitis (rat, rabbit, and mouse), rabbit models with peripherally inserted central catheters (PICC) catheterization, models of PICC/central venous catheter indwelling with combined drugs in human umbilical vein endothelial cells, and compatibility with endothelial cells. Factors affecting vascular endothelial cell injury include difference in the same class of drugs, concentration and exposure time of precipitant, and infusion strategy. Phlebitis is accompanied by endothelial dysfunction and may involve multiple molecular and cellular mechanisms. These findings improve our understanding of the molecular targets of interventions and help identify effective candidates for the prophylaxis and treatment of phlebitis. Vascular health and risk management should be considered when initiating intravenous administration.

Subclinical Vascular Risk Composites Predict Cardiovascular Disease, Stroke, and Dementia: The Multi‐Ethnic Study of Atherosclerosis (MESA)

AbstractBackgroundSubclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for CVD events and dementia beyond conventional risk scores. Therefore, we examined whether subclinical CVD biomarkers: 1) dissociate into composites representing distinct pathologic pathways that 2) predict future risk of clinical CVD, stroke, and dementia‐related outcomes in a diverse longitudinal cohort.MethodMESA followed 6,814 participants (45‐84 years of age) from baseline in 2000‐2002 to 2018 over 6 clinical examinations and annual follow‐up interviews. Baseline subclinical CVD biomarkers were transformed into z‐scores before factor analysis to derive composite factor scores. Time to clinical CVD events (coronary heart disease (CHD) and stroke) and dementia were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI). Global cognitive decline was measured by change in the Cognitive Abilities Screening Instrument from 2010‐12 to 2019‐2021, modeled by linear mixed models, and reported as beta estimates and standard error (SE). Cognitive status was adjudicated in 2019‐2021 as cognitively normal, mild cognitive impairment (MCI) and dementia from Uniform Data Set v3 tests and informant interview and modeled with multinomial logistic regression reported as odds ratios (OR). All models included all factor scores together and adjustment for conventional risk scores: Framingham risk scores for CVD or stroke or Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) for dementia.ResultSubclinical CVD measures aggregated into four distinct factors representing: blood pressure, arterial stiffness, atherosclerosis, and cardiac remodeling (Table 1). Each factor significantly predicted CVD events and dementia independent of each other and conventional risk scores (Figure). Atherosclerosis best predicted time to clinical events of CHD [AUC(95%CI) = 0.73(0.71‐0.75)], stroke [AUC(95%CI) = 0.75(0.70‐0.78)], and dementia [AUC(95%CI) = 0.74(0.71‐0.77)]. Arterial stiffness was the only the factor significantly associated with both cognitive decline (b = ‐0.95, SE = 0.11, p&lt;0.0001), a higher odds of MCI [OR(95%CI) = 1.10(1.01‐1.21)] and dementia [OR(95%CI) = 1.79(1.37‐2.35)] (Table 2). These results were consistent across sex and racial/ethnic groups.ConclusionSubclinical vascular factor composites of arterial stiffness and atherosclerosis shown to independently predict both CVD events and dementia may be useful biomarkers to inform the vascular pathways contributing to Alzheimer’s disease and related dementia etiologies.

Identification of overlay differentially expressed genes in both rats and goats with blast lung injury through comparative transcriptomics

PurposeTo identify the potential target genes of blast lung injury (BLI) for the diagnosis and treatment. MethodsThis is an experimental study. The BLI models in rats and goats were established by conducting a fuel-air explosive power test in an unobstructed environment, which was subsequently validated through hematoxylin-eosin staining. Transcriptome sequencing was performed on lung tissues from both goats and rats. Differentially expressed genes were identified using the criteria of q ≤ 0.05 and |log2 fold change| ≥ 1. Following that, enrichment analyses were conducted for gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathways. The potential target genes were further confirmed through quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay. ResultsObservations through microscopy unveiled the presence of reddish edema fluid, erythrocytes, and instances of focal or patchy bleeding within the alveolar cavity. Transcriptome sequencing analysis identified a total of 83 differentially expressed genes in both rats and goats. Notably, 49 genes exhibited a consistent expression pattern, with 38 genes displaying up-regulation and 11 genes demonstrating down-regulation. Enrichment analysis highlighted the potential involvement of the interleukin-17 signaling pathway and vascular smooth muscle contraction pathway in the underlying mechanism of BLI. Furthermore, the experimental findings in both goats and rats demonstrated a strong association between BLI and several key genes, including anterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4, which exhibited up-regulation. ConclusionsAnterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4 hold potential as target genes for the prognosis, diagnosis, and treatment of BLI.

Comorbidities of Sickle Cell Disease with Obstructive Sleep Apnea

BACKGROUND Sickle cell disease (SCD) is a devastating inherited disease process that greatly impairs quality of life and lifespan. It is a common genetic hemoglobinopathy that is vulnerable to hypoxemia due to the sickling property of red blood cells. Desaturation of the hemoglobin S (HbS) molecule leads to the polymerization of HbS, causing the blockage of microvasculature, oxidative stress, and endothelial damage. The clinical sequelae of SCD include vaso-occlusive crisis, hemolytic episodes, and end-organ damage. Obstructive sleep apnea (OSA) is a common but underdiagnosed condition associated with nocturnal hypoxemia due to intermittent upper airway closure. Repetitive episodes of hypoxemia can cause nocturnal sympathetic activation, selectively activate vascular inflammatory pathways leading to endothelial dysfunction, and can impact cardiac output to predispose patients to ischemia. The impact of this pathophysiology on SCD remains unclear and the literature reviews evaluating the relationship of SCD and OSA are scarce. METHODS We performed a retrospective analysis of the Nationwide Inpatient Sample data in adult patients (age greater than 18 years) hospitalized with SCD as the primary diagnosis in 2020 using ICD-10-CM codes. The NIS is the largest all-payer publicly accessible inpatient healthcare database in the United States. We compared the SCD cohort of 164,990 patients to another consisting of SCD with associated secondary diagnosis of OSA, which consisted of 32,998 patients. The Pearson chi-square test and Student's t test were used to assess categorical and continuous variables, respectively. RESULTS Data revealed that patients diagnosed with SCD and OSA had a statistically significant (p &amp;lt; 0.001) greater incidence of comorbidities compared to SCD alone. These included uncomplicated hypertension (29.8 vs 15.5%), complicated hypertension (24.5 vs 10.6%), uncomplicated diabetes mellitus (9.8 vs 3.4%), complicated diabetes mellitus (17.1 vs 5.1%), obesity (38.9 vs 9.2%), peripheral vascular disease (6.0 vs 3.2%), chronic pulmonary disease (39.7 vs 21.1%), chronic kidney disease (10.0 vs 4.1%), coronary artery disease (15.3 vs 5.1%), and heart failure (13.4 vs 5.4%). Illicit drug use was higher (8.4%) in SCD only compared to SCD with OSA (5.1%). CONCLUSION In this study, co-diagnoses of SCD and OSA revealed a greater likelihood of having other comorbidities, typically 2-3 fold. A striking finding is the increased prevalence of complicated hypertension and diabetes mellitus which are known to give way to vasculopathies, a sequela that is unfavorable in patients with SCD. Considering the clinical implications of these comorbidities and concern for overall underdiagnosis of OSA, it may prove beneficial to lower the threshold for OSA screening in patients with SCD who exhibit hypertension, diabetes, obesity, and other disease processes associated with OSA. Furthermore, should OSA screening in patients with SCD prove favorable, a prospective study evaluating outcomes, such as number of hospitalizations due to sickle cell crisis or acute chest syndrome, of patients diagnosed with OSA and subsequently treated with therapeutic measures such as nocturnal continuous positive airway pressure. Likewise, patients with established co-diagnosis of SCD and OSA should have diligent surveillance and treatment of these aforementioned comorbidities.

Bradycardic effect of endothelial-specific bradykinin type-II receptors overexpression in mice: impact on blood pressure

Abstract Background/Introduction Polymorphisms of the gene encoding for the bradykinin type-II receptors (B2R) has been shown to decrease the expression of B2R and increased vascular resistance and blood pressure in humans. Purpose We aimed to study the role of endothelial B2R on systolic blood pressure (SBP) and heart rate (HR) using a novel mice model with endothelial-specific B2R overexpression (B2tg) as compared with transgene negative littermates (B2n) and on differential expression of proteins potentially relevant to vascular tension. Methods Human and murine B2R expression levels were quantified by rtPCR. Thoracic aortic tissues were used for vascular reactivity studies and proteomic analysis. SBP and HR were measured by the tail-cuff method at baseline, after administration of the COX inhibitor diclofenac (10 mg/kg/day), B2R antagonist icatibant (1 mg/kg) or NOS inhibitor L-NAME (100 mg/kg/day). Results In aortic tissues of B2tg human B2R were exclusively expressed (n=6, P=0.0005), while murine B2R expression levels remained unchanged. Similar results were found in skeletal muscle tissues used as an estimate for resistance vessels. Aortic ring studies revealed a concentration-dependent constriction to bradykinin in wild-type mice (maximal vasoconstriction 9.6±3.0%, n=5) whereas aortic rings of B2tg showed concentration-dependent relaxation (-27.4±4.1%, n=12). SBP was significantly lower in B2tg (125.0 ±1.6 mmHg) as compared to B2n (129.9±1.1 mmHg, n=9, P=0.03). Diclofenac treatment slightly but not significantly reduced SBP in B2n (to 125.5±2.4 mmHg, P=0.09) and in B2tg (to 119.8±2.8 mmHg, n=9, P=0.12), however the difference in SBP remained (P=0.03). In a pilot study, L-NAME administration did also not change the SBP difference between B2n and B2tg (9.9±10.3 mmHg, n=3-4). In contrast, icatibant administration abolished the difference between the groups (B2n 128.6±4.6 vs B2tg 128.3±2.0 mmHg, n=8, P=ns) suggesting the involvement of endothelial B2R in SBP reduction. Interestingly, in the same mice, HR was significantly lower in B2tg (571.4±20.8 bpm) as compared to B2n (626.7±13.7 bpm, P=0.02). While diclofenac didn’t affect HR, icatibant significantly increased HR to (630.8±21.8 bpm in B2tg and 685.5±16.4 bpm in B2n, n=8, P=0.01). Only in B2tg, there was a significant strong correlation between SBP and HR (r=0.76, P=0.016). Analysis of proteomic data revealed differential upregulation of proteins related to cell adhesion (CD44), extracellular matrix (hyaluronidase), and differential downregulation of proteins related to oxidative stress (superoxide dismutase) in B2tg. Conclusion Endothelial B2R overexpression reduces SBP and HR. SBP reduction is not dependent on two major vascular pathways stimulated by products of NOS and COX but appears to be related to endothelial B2R-dependent HR reduction. Hence, agonism at B2R could be a valuable target for development of new cardiovascular drugs.

MiR-135a-5p overexpression in peripheral blood-derived exosomes mediates vascular injury in type 2 diabetes patients.

Diabetes pathology relies on exosomes (Exos). This study investigated how peripheral blood Exo-containing microRNAs (miRNAs) cause vascular injury in type 2 diabetes (T2D). We removed DEmiRNA from T2D chip data from the GEO database. We isolated Exo from 15 peripheral blood samples from T2D patients and 15 healthy controls and measured Exo DEmiRNA levels. We employed the intersection of Geneards and mirWALK database queries to find T2D peripheral blood mRNA-related chip target genes. Next, we created a STRING database candidate target gene interaction network map. Next, we performed GO and KEGG enrichment analysis on T2D-related potential target genes using the ClusterProfiler R package. Finally, we selected T2D vascular damage core genes and signaling pathways using GSEA and PPI analysis. Finally, we used HEK293 cells for luciferase assays, co-cultured T2D peripheral blood-derived Exo with HVSMC, and detected HVSMC movement alterations. We found 12 T2D-related DEmiRNAs in GEO. T2D patient-derived peripheral blood Exo exhibited significantly up-regulated miR-135a-3p by qRT-PCR. Next, we projected miR-135a-3p's downstream target mRNA and screened 715 DEmRNAs to create a regulatory network diagram. DEmRNAs regulated biological enzyme activity and vascular endothelial cells according to GO function and KEGG pathway analysis. ErbB signaling pathway differences stood out. PPI network study demonstrated that DEmRNA ATM genes regulate the ErbB signaling pathway. The luciferase experiment validated miR-135a-3p and ATM target-binding. Co-culture of T2D patient-derived peripheral blood Exo with HVSMC cells increases HVSMC migration, ErbB2, Bcl-2, and VEGF production, and decreases BAX and ATM. However, miR-135a-3p can reverse the production of the aforesaid functional proteins and impair HVSMC cell movement. T2D patient-derived peripheral blood Exo carrying miR-135a-3p enter HVSMC, possibly targeting and inhibiting ATM, activating the ErbB signaling pathway, promoting abnormal HVSMC proliferation and migration, and aggravating vascular damage.

6 Posterior cerebral artery-defined white matter hyperintensities are associated with object domain memory and transentorhinal volume independently of global beta-amyloid burden

Objective:White matter hyperintensities (WMH) are a radiological marker of small vessel cerebrovascular disease that are related to cognition and memory decline in aging and Alzheimer’s disease (AD). However, the mechanisms that link WMH to memory impairment and whether they interact with or act independently of AD pathophysiology are unclear. The transentorhinal cortex (BA35) is among the earliest anatomical regions to show tau deposition and subsequent atrophy, and baseline posterior WMH is related to longitudinal cortical thinning of the entorhinal cortex. However, it is unclear whether regional WMH are related to BA35 volume specifically, and whether this relationship is influenced by amyloid-β (Aβ) burden. We hypothesized that WMH in the vascular territory of the posterior cerebral artery (PCA), which perfuses both posterior and medial temporal lobe regions, would be associated with reduced BA35 volume and with lower memory in older adults independently of Aβ.Participants and Methods:114 older adults without dementia, aged 60 to 98 years (mean (SD) = 78.31 (11.02), 71 (62.8%) women), were included. Regional WMH volumes were derived from T2-FLAIR images using ANTs, a vascular territory atlas and manual editing. Global Aβ was assessed with 18F-florbetapir PET, using SUVR of a cortical composite region (FBP mean SUVR) with a cerebellar reference region. Total transentorhinal (BA35) volume was derived using T1 and T2-weighted images using ASHS. To assess hippocampal pattern separation ability, an index of episodic memory, participants completed both object (MDT-O) and spatial (MDT-S) versions of a mnemonic discrimination task, with the lure discrimination index as the outcome. Using linear regressions, we first tested for associations among PCA-defined WMH, Aβ, BA35 volume, and MDT-S and MDT-O scores. We then tested whether the relationship between PCA-defined WMH and MDT-O performance was mediated by BA35 volume and whether this mediation was moderated by Aβ. All models adjusted for age, sex, and education.Results:PCA-defined WMH were related to higher FBP mean SUVR (b=0.287, p=0.042) and lower BA35 volume (b=-0.222, p=0.038). PCA-defined WMH were also negatively related to MDT-O performance (b=-0.229, p=0.044), but not to MDT-S (b=-0.171, p=0.118). FBP mean SUVR was not related to BA35 volume (b=-0.131, p=0.344) or MDT performance (MDT-S: b=-0.138, p=0.348; MDT-O: b=0.059, p=0.690). Furthermore, FBP mean SUVR did not interact with PCA-defined WMH to predict memory performance (interaction b=-0.039, p=0.973), nor BA35 volume (interaction b=-0.140, p=0.894). The association of PCA-defined WMH to MDT-O was fully mediated by BA35 volume (indirect effect b=-0.0005, 95% CI (-0.0014, -0.0003)). This mediation was not moderated by FBP mean SUVR (indirect effect b=-0.00001, 95% CI (-0.001, 0.001)).Conclusions:We found that PCA-defined WMH were related to memory performance in older adults, and this association is fully mediated by transentorhinal volume. While PCA-defined WMH are related to higher global Aβ burden, there is no interaction between PCA-defined WMH and Aβ on BA35 volume. These findings point to an amyloid-independent vascular pathway towards memory decline in aging and AD. Future work should examine whether the pathway linking PCA-defined WMH to transentorhinal cortex atrophy and subsequent memory decline is mediated by regional tau pathology.

Waterborne Tebuconazole Exposure Induces Male-Biased Sex Differentiation in Zebrafish (Danio rerio) Larvae via Aromatase Inhibition.

Tebuconazole is a widely used fungicide for various crops that targets sterol 14-α-demethylase (CYP51) in fungi. However, attention has shifted to aromatase (CYP19) due to limited research indicating its reproductive impact on aquatic organisms. Herein, zebrafish were exposed to 0.5 mg/L tebuconazole at different developmental stages. The proportion of males increased significantly after long-term exposure during the sex differentiation phase (0-60, 5-60, and 19-60 days postfertilization (dpf)). Testosterone levels increased and 17β-estradiol and cyp19a1a expression levels decreased during the 5-60 dpf exposure, while the sex ratio was equally distributed on coexposure with 50 ng/L 17β-estradiol. Chemically activated luciferase gene expression bioassays determined that the male-biased sex differentiation was not caused by tebuconazole directly binding to sex hormone receptors. Protein expression and phosphorylation levels were specifically altered in the vascular endothelial growth factor signaling pathway despite excluding the possibility of tebuconazole directly interacting with kinases. Aromatase was selected for potential target analysis. Molecular docking and aromatase activity assays demonstrated the interactions between tebuconazole and aromatase, highlighting that tebuconazole poses a threat to fish populations by inducing a gender imbalance.

Hydrogen sulfide donor activates AKT-eNOS signaling and promotes lymphatic vessel formation.

The lymphatic network is pivotal for various physiological functions in the human body. Accumulated evidence supports the role of therapeutic lymphangiogenesis in the treatment of several pathologies. Endogenous gasotransmitter, hydrogen sulfide (H2S) has been extensively studied for its potential as a pro-angiogenic factor and vascular function modulator. However, the role of H2S in governing lymphatic vessel formation, and underlying molecular mechanisms are understudied. The present study was designed to investigate the effects of H2S donor sodium hydrogen sulfide (NaHS) on lymphatic vascularization and pro-angiogenic signaling pathways using both in vitro and in vivo approaches. In vitro dose-response experiments showed increased proliferation and tube formation by NaHS-treated human lymphatic endothelial cells (LECs) compared with control cells. Immunoblotting performed with LEC lysates prepared after time-course NaHS treatment demonstrated increased activation of ERK1/2, AKT and eNOS after 20 min of NaHS stimulation. Further, NaHS treatment induced nitric oxide production, reduced reactive oxygen species generation, and promoted cell cycle in LECs. Additional cell cycle analysis showed that NaHS treatment abrogates oxidized LDL-induced cell cycle arrest in LECs. The results of in vivo Matrigel plug assay revealed increased lymphatic vessel density in Matrigel plugs containing NaHS compared with control plugs, however, no significant differences in angiogenesis and immune cell infiltration were observed. Collectively, these findings suggest that H2S donor NaHS promotes lymphatic vessel formation both in vitro and in vivo and may be utilized to promote reparative lymphangiogenesis to alleviate lymphatic dysfunction-related disorders.

Exploring the Molecular and Developmental Dynamics of Endothelial Cell Differentiation.

The development and differentiation of endothelial cells (ECs) are fundamental processes with significant implications for both health and disease. ECs, which are found in all organs and blood vessels, play a crucial role in facilitating nutrient and waste exchange and maintaining proper vessel function. Understanding the intricate signaling pathways involved in EC development holds great promise for enhancing vascularization, tissue engineering, and vascular regeneration. Hematopoietic stem cells originating from hemogenic ECs, give rise to diverse immune cell populations, and the interaction between ECs and immune cells is vital for maintaining vascular integrity and regulating immune responses. Dysregulation of vascular development pathways can lead to various diseases, including cancer, where tumor-specific ECs promote tumor growth through angiogenesis. Recent advancements in single-cell genomics and in vivo genetic labeling have shed light on EC development, plasticity, and heterogeneity, uncovering tissue-specific gene expression and crucial signaling pathways. This review explores the potential of ECs in various applications, presenting novel opportunities for advancing vascular medicine and treatment strategies.

Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol

Preterm labour is a birth that occurs between 22 and 37 weeks after conception. The primary cause of infant death is preterm birth (PTD), which is linked to long-term neurodevelopmental and behavioural effects for preterm survivors. A maternal vascular disease pathway and an inflammation/infection pathway are two suggested pathways that have collected sufficient evidence. The identification of women who are more likely to develop PTD and the understanding of the underlying physiological mechanisms would be made possible by reliable biomarkers for these pathways. Systemic maternal infections cause elevated levels of inflammatory cytokines, which then drive the creation of prostaglandins, which can cause cervical ripening and uterine contractions that result in preterm birth. Women with signs of preterm labour have been found to have high serum levels of proinflammatory which have been prospectively linked to preterm birth. A non-specific biomarker of inflammation, C-reactive protein (CRP) is an acute phase reactant in the innate immune response. The production of C-reactive protein, a serological marker that is readily identifiable, occurs largely in the hepatocytes in response to cytokine releases from the inflammatory site. Cytokines released, by an intrauterine infection go through the maternal bloodstream to the liver, where they activate the production of CRP. Forty-eight hours after stimulation the acute-phase response has reached its maximum and a meaningful measurement can be made from a blood sample. Although the exact cause of inflammation is unknown, modest and long-lasting elevations of CRP have been linked to a range of illnesses, including normal pregnancy. Elevated CRP levels in the peripheral circulation have been connected to the presence of intrauterine infection. It has been investigated to diagnose subclinical infections using the maternal CRP concentration. The purpose of this study is to determine the link between maternal serum CRP and subsequent preterm birth in single pregnant women.