Feto-placental endothelial dysfunction in Gestational Diabetes Mellitus under dietary or insulin therapy.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a serious complication in pregnancy. Despite controlling the plasma glucose levels with dietary intervention (GDM-D) or insulin therapy (GDM-I), children born of diabetic mothers suffer more long-term complications from childhood to early adulthood. Placental circulation and nutrient exchange play a vital role in fetal development. Additionally, placental endothelial function is an indicator of vascular health, and plays an important role in maintaining placental circulation for nutrient exchange. This study was conducted to assess changes in fetal endothelial dysfunction in GDM under different interventions during pregnancy. METHODS: The primary human umbilical vein endothelial cells (HUVECs) were obtained from normal pregnant women (n = 11), GDM-D (n = 14), and GDM-I (n = 12) patients. LC-MS/MS was used to identify differentially expressed proteins in primary HUVECs among the three groups, after which Bioinformatics analysis was performed. Glucose uptake, ATP level, apoptosis, and differentially expressed proteins were assessed to investigate changes in energy metabolism. RESULTS: A total of 8174 quantifiable proteins were detected, and 142 differentially expressed proteins were identified after comparing patients with GDM-D/GDM-I and healthy controls. Of the 142, 64 proteins were upregulated while 77 were downregulated. Bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes and signaling pathways related to cellular processes, biological regulation, and metabolic processes. According to the results from KEGG analysis, there were changes in the PI3K/AKT signaling pathway after comparing the three groups. In addition, there was a decrease in glucose uptake in the GDM-I (P < 0.01) group. In GDM-I, there was a significant decrease in the levels of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3). Moreover, glucose uptake was significantly decreased in GDM-I, although in GDM-D, there was only a decrease in the levels of GLUT1. ATP levels decreased in GDM-I (P < 0.05) and apoptosis occurred in both the GDM-D and GDM-I groups. Compared to the normal controls, the levels of phosphate AKT and phosphate AMPK over total AKT and AMPK were reduced in the GDM-I group. CONCLUSION: In summary, endothelial dysfunction occurred in pregnancies with GDM even though the plasma glucose levels were controlled, and this dysfunction might be related to the degree of glucose tolerance. The energy dysfunction might be related to the regulation of the AKT/AMPK/mTOR signaling pathway.

Endothelial thioredoxin interacting protein (TXNIP) modulates endothelium-dependent vasorelaxation in hyperglycemia.

Endothelial dysfunction, hallmarked by an imbalance between vasoconstriction and vasorelaxation, is associated with diabetes. Thioredoxin Interacting protein (TXNIP), controlled by an exquisitely glucose sensitive gene, is increasingly recognized for its role in diabetes. However, the role of TXNIP in modulating diabetes-related endothelial dysfunction remains unclear. To elucidate the role of TXNIP, we generated two novel mouse strains; endothelial-specific TXNIP knockout (EKO) and a Tet-O inducible, endothelial-specific TXNIP overexpression (EKI). Hyperglycemia was induced by streptozotocin (STZ) treatment in floxed control (fl/fl) and EKO mice. Doxycycline (DOX) was given to EKI mice to induce endothelial TXNIP overexpression. The ablation of endothelial TXNIP improved glucose tolerance in EKO mice. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in STZ-treated fl/fl mice while this STZ impaired vasorelaxation was attenuated in EKO mice. Hyperglycemia induction of NLRP3 and reductions in Akt and eNOS phosphorylation were also mitigated in EKO mice. Overexpression of endothelial TXNIP did not impair glucose tolerance in DOX-treated EKI mice, however induction of endothelial TXNIP led to impaired vasorelaxation in EKI mice. This was associated with increased NLRP3 and reduced Akt and eNOS activation. In conclusion, deletion of endothelial TXNIP is protective against and overexpression of endothelial TXNIP induces endothelial dysfunction; thus, endothelial TXNIP plays a critical role in modulating endothelial dysfunction.

IL-15 induced bystander activation of CD8+ T cells may mediate endothelium injury through NKG2D in Hantaan virus infection.

Introduction: Hantaan virus (HTNV) can cause endothelium injury in hemorrhagic fever with renal syndrome (HFRS) patients. Bystander activation of CD8+ T cells by virus infection has been shown that was involved in host injury, but it is unclear during HTNV infection. This project aimed to study the effect of bystander-activated CD8+ T cell responses in HTNV infection. Methods: The in vitro infection model was established to imitate the injury of endothelium in HFRS patients. Flow cytometry was performed to detect the expression of markers of tetramer+ CD8+ T cells and human umbilical vein endothelial cells (HUVECs). The levels of interleukin-15 (IL-15) in serum and supermanant were detected using ELISA kit. The expression of MICA of HUVECs was respectively determined by flow cytometry and western blot. The cytotoxicity of CD8+ T cells was assessed through the cytotoxicity assay and antibody blocking assay. Results: EBV or CMV-specific CD8+ T cells were bystander activated after HTNV infection in HFRS patients. HTNV-infected HUVECs in vitro could produce high levels of IL-15, which was positively correlated with disease severity and the expression of NKG2D on bystander-activated CD8+ T cells. Moreover, the elevated IL-15 could induce activation of CD122 (IL-15Rß)+NKG2D+ EBV/CMV-specific CD8+ T cells. The expression of IL-15Rα and ligand for NKG2D were upregulated on HTNV-infected HUVECs. Bystander-activated CD8+ T cells could exert cytotoxicity effects against HTNV-infected HUVECs, which could be enhanced by IL-15 stimulation and blocked by NKG2D antibody. Discussion: IL-15 induced bystander activation of CD8+ T cells through NKG2D, which may mediate endothelium injury during HTNV infection in HFRS patients.

Endothelial Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

OBJECTIVES: To review, analyze, and synthesize the literature on endothelial dysfunction in critically ill children with multiple organ dysfunction syndrome and to develop a consensus biomarker-based definition and diagnostic criteria. DATA SOURCES: Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, using a combination of medical subject heading terms and key words to define concepts of endothelial dysfunction, pediatric critical illness, and outcomes. STUDY SELECTION: Studies were included if they evaluated critically ill children with endothelial dysfunction, evaluated performance characteristics of assessment/scoring tools to screen for endothelial dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants (≤36 weeks gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and non-English language studies with the inability to determine eligibility criteria were excluded. DATA EXTRACTION: Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment. DATA SYNTHESIS: We identified 62 studies involving 84 assessments of endothelial derived biomarkers indirectly linked to endothelial functions including leukocyte recruitment, inflammation, coagulation, and permeability. Nearly all biomarkers studied lacked specificity for vascular segment and organ systems. Quality assessment scores for the collected literature were low. CONCLUSIONS: The Endothelial Subgroup concludes that there exists no single or combination of biomarkers to diagnose endothelial dysfunction in pediatric multiple organ dysfunction syndrome. Future research should focus on biomarkers more directly linked to endothelial functions and with specificity for vascular segment and organ systems.

Novel biomarker panel measuring endothelial injury identifies patients at risk of coronary artery syndrome and discordance with low-density lipoprotein cholesterol.

BACKGROUND: Individuals with no history of coronary artery disease can develop acute coronary syndrome (ACS), often in the absence of major risk factors including low-density lipoprotein cholesterol (LDL-C). We identified risk factors and biomarkers that can help identify those at discordantly high risk of ACS with normal LDL-C using a novel validated coronary artery disease predictive algorithm (CADPA) incorporating biomarkers of endothelial injury. METHODS: Five-year predicted ACS risk was calculated for 6392 persons using CADPA. Persons were classified as low (<3.5%), intermediate (3.5-<7.5%) or high (≥7.5%) CADPA risk and by LDL-C levels <130 mg/dL (low) and ≥130 mg/dL (high) and whether in the discordantly low LDL-C (but high CADPA risk) or high LDL-C (but low/intermediate CADPA risk) group. Multiple logistic regression identified risk factors and biomarkers that predicted discordance. RESULTS: 31% were classified as low (<3.5%), 27% at intermediate (3.5-<7.5%) and 42% were at high risk (≥7.5%). 28% of subjects were identified in the low LDL discordant risk group (LDL-C< 130 mg/dL but 5-year CADPA predicted risk ≥7.5%) and 19% in the high LDL discordant risk group (LDL-C ≥ 130 mg/dL but 5-year CADPA risk of <7.5%). Diabetes (odds ratio [OR], 2.84 [2.21-3.66]), male sex (OR, 2.83 [2.40-3.35]), family history (OR, 2.23 [1.88-2.64]) and active smoking (OR, 1.99 [1.50-2.62]) predicted low LDL risk discordance more than other risk factors (all P < 0.01). Increased serum soluble FAS, hemoglobin A1c and interleukin-16 were the biomarkers most independently associated with increased risk. CONCLUSIONS: Discordance between LDL-C levels and ACS risk is common. Males with diabetes and a family history of myocardial infarction who are actively smoking may be at highest risk of developing ACS despite controlled LDL-C. Future studies should examine whether using the CADPA can help identify individuals that could benefit from earlier targeting of risk factor modification for the prevention of ACS.

Viral Endothelial Dysfunction: A Unifying Mechanism for COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible virus with significant global impact, morbidity, and mortality. The SARS-CoV-2 virus may result in widespread organ manifestations including acute respiratory distress syndrome, acute renal failure, thromboembolism, and myocarditis. Virus-induced endothelial injury may cause endothelial activation, increased permeability, inflammation, and immune response and cytokine storm. Endothelial dysfunction is a systemic disorder that is a precursor of atherosclerotic vascular disease that is associated with cardiovascular risk factors and is highly prevalent in patients with atherosclerotic cardiovascular and peripheral disease. Several studies have associated various viral infections including SARS-CoV-2 infection with inflammation, endothelial dysfunction, and subsequent innate immune response and cytokine storm. Noninvasive monitoring of endothelial function and identification of high-risk patients who may require specific therapies may have the potential to improve morbidity and mortality associated with subsequent inflammation, cytokine storm, and multiorgan involvement.

A body shape index is associated with endothelial dysfunction in both men and women.

A body shape index (ABSI) was proposed for estimation of abdominal adiposity. ABSI has been reported to have associations with cardiovascular risk factors and cardiovascular events. However, there is no information on the association between ABSI and endothelial function. We examined cross-sectional associations of ABSI with endothelial function in 8823 subjects (6773 men and 2050 women). Subjects with a lower quartile of flow-mediated vasodilation (FMD) were defined as subjects having endothelial dysfunction. Pearson's correlation coefficient analysis revealed that ABSI was negatively correlated with FMD (men, r = - 0.23, P = 0.003; women, r = - 0.32, P < 0.001). The areas under the curves of ABSI and body mass index to predict endothelial dysfunction were 0.64 (95% confidence interval [CI] 0.62-0.65) and 0.58 (95% CI 0.57-0.60) in men, and 0.68 (95% CI 0.66-0.71) and 0.59 (95% CI 0.56-0.61) in women, respectively. The cutoff values of ABSI for predicting subjects with endothelial dysfunction were 0.0796 (sensitivity, 55.2%; specificity, 65.5%) in men and 0.0823 (sensitivity, 56.2%; specificity, 73.4%) in women. Multivariate analysis revealed that an ABSI value higher than the cutoff value remained an independent predictor of endothelial dysfunction in both sexes. The results of our study suggest that ABSI calculation should be performed for evaluation of risk of cardiovascular events in both men and women.Clinical trial registration information URL for Clinical Trial: https://www.umin.ac.jp/ctr/index.htm ; Registration Number for Clinical Trial: UMIN000012952 (01/05/2010).

Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation.

Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17-19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

Endothelial dysfunction and Mid-Regional proAdrenomedullin: What role in SARS-CoV-2 infected Patients?

BACKGROUND: Endothelial dysfunction, a major complication of SARS-CoV-2 infectionplaying a key-role in multi-organ damage, carries high risk of mortality. AIM: To investigate the potential role of Mid-Regional pro-Adrenomedullin (MR-proADM) in detecting endothelial damage with a view to stratifying the risk of adverse events (length of stay, death, admission in Intensive Care Unit) and/or disease resolution. MATERIALS AND METHODS: In 135 consecutive patients with SARS-CoV-2 infection, MR-proADM was measured in EDTA-K2 plasma samples using B.R.A.H.M.S. KRYPTOR® COMPACT Plus method (Thermo Fisher Scientific, Hennigsdorf, Germany) RESULTS: Patients were subdivided into three groups based on their MR-proADM value (nmol/L): 1 (n = 20, MR-proADM ≤ 0.55); 2 (n = 82, 0.55 < MR-proADM ≤ 1.50); 3 (n = 33, MR-proADM > 1.50). The higher the MR-proADM value, the greater the patients' age, the more frequent the occurrence of pneumonia, the requiring of more aggressive treatment, the longer the hospitalization and the more frequent a fatal event. Significant differences were found between the three groups for MR-proADM, White-blood cell count, Neutrophil count, D-dimer, C-reactive Protein, Procalcitonin and hs-Troponin I. At logistic regression,it was found that MR-proADM and Log10D-dimer were the most significant predictors of adverse events. CONCLUSION: The findings made in the present study highlight the relevance of MR-proADM values in providing clinically useful information, particularly for stratifying COVID-19 patients according to the risk of a more severe form of disease and to the development of adverse events.

El endotelio como órgano diana en la fisiopatología y la terapéutica de la hipertensión arterial / The endothelium as a target organ in pathophysiology and therapy of arterial hypertension

Hemos leído con gran atención el artículo de los autores González Rey y otros, titulado: Disfunción endotelial en una etapa precoz del diagnóstico de hipertensión arterial. Resulta muy interesante el tratamiento de un tema básico de gran interés en la clínica a través del uso de biomarcadores casi siempre a la disposición de nuestros profesionales de la salud en los diferentes niveles de atención como resulta ser el caso de la microalbuminuria.1 El endotelio resulta cada vez de mayor interés para investigadores y médicos de asistencia, pues es el punto de confluencia de las enfermedades vasculares, metabólicas y neurodegenerativas, y es el primer eslabón en el desarrollo de la aterosclerosis. Se conoce que los diferentes factores involucrados en la activación y daño endotelial como las altas concentraciones de ácido úrico,2 los niveles elevados de ácidos grasos,3 el envejecimiento4 y la hiperglicemia,5 son los mismos que contribuyen a posteriori con el desarrollo y las complicaciones de la placa de ateroma. Vale destacar el aporte...(AU)

Patient-specific iPSC-derived endothelial cells reveal aberrant p38 MAPK signaling in atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with high morbidity and mortality. Existing evidence suggests that the central pathogenesis to aHUS might be endothelial cell damage. Nevertheless, the role of endothelial cell alterations in aHUS has not been well characterized and the underlying mechanisms remain unclear. Utilizing an induced pluripotent stem cell-derived endothelial cell (iPSC-EC) model, we showed that anti-complement factor H autoantibody-associated aHUS patient-specific iPSC-ECs exhibited an intrinsic defect in endothelial functions. Stimulation using aHUS serums exacerbated endothelial dysfunctions, leading to cell apoptosis in iPSC-ECs. Importantly, we identified p38 as a novel signaling pathway contributing to endothelial dysfunctions in aHUS. These results illustrate that iPSC-ECs can be a reliable model to recapitulate EC pathological features, thus providing a unique platform for gaining mechanistic insights into EC injury in aHUS. Our findings highlight that the p38 MAPK signaling pathway can be a therapeutic target for treatment of aHUS.

Changes in the Biomarkers of Oxidative/Nitrosative Stress and Endothelial Dysfunction Are Associated with Cardiovascular Risk in Periodontitis Patients.

Patients with cardiovascular disease (CVD) and periodontitis (PT) show shared risk factors as result of the altered molecular mechanisms associated with pathological conditions. The aim of our study was to evaluate if the plasma biomarkers associated with endothelial dysfunction may also be related to alterations in the inflammatory status in peripheral blood mononuclear cells (PBMC). Patients with PT, coronary heart disease (CHD), or both diseases as well as controls were enrolled. Plasma levels of coenzyme Q10 (CoQ10), 3-nitrotyrosine (NT), and asymmetric dimethylarginine (ADMA) were assessed using HPLC. mRNA levels of caspase-1 (CASP1), NLR family pyrin domain containing 3 (NLRP3), and tumor necrosis factor-α (TNF-α) in PBMC from the recruited subjects were quantified using real-time PCR. Patients with PT + CHD showed lower CoQ10 plasma levels and increased concentrations of NT in comparison to healthy subjects. ADMA levels were higher in CHD and PT + CHD patients compared to controls. Transcript levels of CASP1, NLRP3, and TNF-α were up-regulated in PBMC from all patient groups when compared to healthy subjects. Our results suggest a possible causal link between oxidative stress, high levels of NT and ADMA, and inflammasome activation, which may be involved in the endothelial inflammatory dysfunction leading to the pathogenesis and progression of CHD in PT patients.

Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia.

Soluble Fms-like tyrosine kinase (sFlt-1/sVEGFR1) is a naturally occurring antagonist of vascular endothelial growth factor (VEGF). Despite being a secreted, soluble protein lacking cytoplasmic and transmembrane domains, sFlt-1 can act locally and be protective against excessive microenvironmental VEGF concentration or exert autocrine functions independently of VEGF. Circulating sFlt-1 may indiscriminately affect endothelial function and the microvasculature of distant target organs. The clinical significance of excess sFlt-1 in kidney disease was first shown in preeclampsia, a major renal complication of pregnancy. However, circulating sFlt-1 levels appear to be increased in various diseases with varying degrees of renal impairment. Relevant clinical associations between circulating sFlt-1 and severe outcomes (e.g., endothelial dysfunction, renal impairment, cardiovascular disease, and all-cause mortality) have been observed in patients with CKD and after kidney transplantation. However, sFlt-1 appears to be protective against renal dysfunction-associated aggravation of atherosclerosis and diabetic nephropathy. Therefore, in this study, we provide an update on sFlt-1 in several kidney diseases other than preeclampsia, discuss clinical findings and experimental studies, and briefly consider its use in clinical practice.

Effect of Stent Strut Interval on Neointima Formation After Venous Stenting in an Ovine Model.

OBJECTIVE: The impact of stent design on venous patency is not well studied. The purpose of this study was to investigate the effect of stent material burden on endothelial coverage of stented venous segments, which may contribute to vessel healing and patency. METHODS: Segmented self expanding bare nitinol stents (18 × 50 mm) comprising 5 mm long attached metallic rings separated by 2, 5, or 8 mm gaps were implanted in the inferior vena cava (IVC) of 10 sheep. These stents were designed and manufactured for the purposes of this study. At six, 12, and 24 weeks after implantation the animals were euthanised and the stented vessels harvested for histomorphometric analysis. Three sections from the metallic part as well as the gaps between the struts were reviewed for quantification of endothelialisation after six, 12, and 24 weeks. The intimal thickness over and between the stent struts was measured. The endothelialisation score (graded from 1 for complete luminal endothelialisation to 5 for absence of endothelial cells) was determined. RESULTS: All stents were successfully deployed and all 10 sheep survived until the time of harvesting. Macroscopic inspection after 24 weeks showed only partial endothelialisation over stents with 2 mm and 5 mm skipped segments, whereas the stents with 8 mm skipped segments were totally incorporated into the vein wall. After 24 weeks, the mean (SD) neointimal thicknesses over stent struts with 2 mm, 5 mm, and 8 mm skipped segments were 254.0 (51.6), 182.2 (98.1), and 194.6 (101.1) µm, respectively. Comparison of endothelialisation scores of stents over time showed statistically significantly better endothelialisation over stents with 8 mm gaps after 12 and 24 weeks. CONCLUSION: Stent designs providing structural support to veins with larger gaps between the scaffold material appear to lead to faster and more complete endothelialisation as well as a thinner intimal layer.

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.

Race-specific changes in endothelial inflammation and microRNA in response to an acute inflammatory stimulus.

Both aberrant vascular reactivity to acute cardiovascular stress and epigenetic mechanisms such as microRNA (miR) may underlie the increased propensity for African Americans (AA) to develop cardiovascular disease. This study assessed racial differences in acute induced endothelial inflammation and related miRs. Cultured human umbilical vein endothelial cells (HUVECs) derived from AA and Caucasian Americans (CA) were exposed to influenza vaccine to determine changes in inflammatory markers, endothelial nitric oxide synthase (eNOS), and miR expression/release. Endothelial function [flow-mediated dilation (FMD)], circulating IL-6, and circulating miR were also measured in young, healthy AA and CA individuals before and after receiving the influenza vaccine. There were no significant racial differences in any parameters at baseline. The vaccine induced increases in IL-6 release (24%, P = 0.02) and ICAM-1 mRNA (40%, P = 0.03), as well as reduced eNOS mRNA (24%, P = 0.04) in AA HUVECs, but not in CA HUVECs (all P > 0.05). Intracellular levels of anti-inflammatory miR-221-3p and miR-222-3p increased specifically in CA HUVECs (72% and 53%, P = 0.04 and P = 0.06), whereas others did not change in either race. HUVEC secretion of several miRs decreased in both races, whereas the release of anti-inflammatory miR-150-5p was decreased only by AA cells (-30%, P = 0.03). In individuals of both races, circulating IL-6 increased approximately twofold 24 h after vaccination (both P < 0.01) and returned to baseline levels by 48 h, whereas FMD remained unchanged. Although macrovascular function was unaffected by acute inflammation in AA and CA individuals, AA endothelial cells exhibited increased susceptibility to acute inflammation and unique changes in related miR.NEW & NOTEWORTHY Used as an acute inflammatory stimulus, the influenza vaccine induced an inflammatory response and decreased eNOS gene expression in endothelial cells derived from African Americans, but not Caucasian Americans. Race-specific changes in intracellular expression and release of specific microRNAs also occurred and may contribute to an exaggerated inflammatory response in African Americans. In vivo, the vaccine caused similar systemic inflammation but had no effect on endothelial function or circulating microRNAs in individuals of either race.

Coronary microvascular adaptations distal to epicardial artery stenosis.

Until recently, epicardial coronary stenosis has been considered the primary outcome of coronary heart disease, and clinical interventions have been dedicated primarily to the identification and removal of flow-limiting stenoses. However, a growing body of literature indicates that both epicardial stenosis and microvascular dysfunction contribute to damaging myocardial ischemia. In this review, we discuss the coexistence of macro- and microvascular disease, and how the structure and function of the distal microcirculation is impacted by the hemodynamic consequences of an epicardial, flow-limiting stenosis. Mechanisms of endothelial dysfunction as well as alterations of smooth muscle function in the coronary microcirculation distal to stenosis are discussed. Risk factors including diabetes, metabolic syndrome, and aging exacerbate microvascular dysfunction in the myocardium distal to a stenosis, and our current understanding of the role of these factors in limiting collateralization and angiogenesis of the ischemic myocardium is presented. Importantly, exercise training has been shown to promote collateral growth and improve microvascular function distal to stenosis; thus, the current literature reporting the mechanisms that underlie the beneficial effects of exercise training in the microcirculation distal to epicardial stenosis is reviewed. We also discuss recent studies of therapeutic interventions designed to improve microvascular function and stimulate angiogenesis in clinically relevant animal models of epicardial stenosis and microvascular disease. Finally, microvascular adaptation to removal of epicardial stenosis is considered.

Endothelial TLR2 promotes proangiogenic immune cell recruitment and tumor angiogenesis.

Toll-like receptor 2 (TLR2) is implicated in various pathologies, mainly in terms of its function within innate immune cells. However, TLR2 is also present in endothelial cells. Here, we explored the physiological and pathophysiological roles of endothelial TLR2 signaling. We found that TLR2 was highly abundant in the endothelium within various tissues using TLR2-IRES-EGFP reporter mice and was required for proinflammatory endothelial cell function. Endothelial cells lacking TLR2 exhibited reduced proinflammatory potential at the protein, cell, and tissue levels. Loss of endothelial TLR2 blunted the inflammatory response to both exogenous and endogenous danger signals in endothelial cells in culture and in vivo. Endothelial TLR2 promoted tumor growth, angiogenesis, and protumorigenic immune cell recruitment in a mouse model of prostate cancer. Furthermore, the cell surface localization of P-selectin and the subsequent production of other critical cell adhesion molecules (such as E-selectin, ICAM-1 and VCAM-1) that recruit immune cells required endothelial TLR2. Our findings demonstrate that endothelial cells actively contribute to innate immune pathways and propose that endothelial TLR2 has a pathological role in proinflammatory conditions.

The cold receptor TRPM8 activation leads to attenuation of endothelium-dependent cerebral vascular functions during head cooling.

Using the cranial window technique, we investigated acute effects of head cooling on cerebral vascular functions in newborn pigs. Head cooling lowered the rectal and extradural brain temperatures to 34.3 ± 0.6°C and 26.1 ± 0.6°C, respectively. During the 3-h hypothermia period, responses of pial arterioles to endothelium-dependent dilators bradykinin and glutamate were reduced, whereas the responses to hypercapnia and an endothelium-independent dilator sodium nitroprusside (SNP) remained intact. All vasodilator responses were restored after rewarming, suggesting that head cooling did not produce endothelial injury. We tested the hypothesis that the cold-sensitive TRPM8 channel is involved in attenuation of cerebrovascular functions. TRPM8 is immunodetected in cerebral vessels and in the brain parenchyma. During normothermia, the TRPM8 agonist icilin produced constriction of pial arterioles that was antagonized by the channel blocker AMTB. Icilin reduced dilation of pial arterioles to bradykinin and glutamate but not to hypercapnia and SNP, thus mimicking the effects of head cooling on vascular functions. AMTB counteracted the impairment of endothelium-dependent vasodilation caused by hypothermia or icilin. Overall, mild hypothermia produced by head cooling leads to acute reversible reduction of selected endothelium-dependent cerebral vasodilator functions via TRPM8 activation, whereas cerebral arteriolar smooth muscle functions are largely preserved.

Chronic Allograft Injury.

With the incremental improvements in long-term kidney transplant survival, there is renewed focus on what causes failure of the transplanted allograft. Over the past decade, our understanding of the injuries that lead to loss of graft function over time has evolved. Chronic allograft injury includes both immune-mediated and nonimmune-mediated injuries, which may involve the organ donor, the recipient, or both. The targets of injury include the kidney tubular epithelium, the endothelium, and the glomerulus. As a response to injury, there are the expected tissue remodeling and repair processes. However, if inflammation persists, which is not uncommon in the transplant setting, the resulting maladaptive response is matrix deposition and/or fibrosis. This ultimately leads to declining graft function and, finally, failure. With our advancing knowledge of the multiple etiologies and mechanisms, enhanced by more recent cohort studies in humans, there is an opportunity to identify those at greater risk to initiate new strategies to ameliorate the process. Although the most recent studies focus on immune-mediated injuries, there is a critical need to identify both markers of injury and mechanisms of injury. In this review, we highlight the findings of recent studies, highlight the potential therapeutic targets, and identify the continued unmet need for understanding the mechanisms of late graft failure.