CD4+ TH cells develop into subsets that are specialized in the secretion of particular cytokines to mediate restricted types of inflammation and immune responses. Among the subsets that promote ...development of allergic inflammatory responses, IL-9-producing TH9 cells are regulated by a number of transcription factors. We have previously shown that the E26 transformation-specific (Ets) family members PU.1 and Ets translocation variant 5 (ETV5) function in parallel to regulate IL-9. In this study we identified a third member of the Ets family of transcription factors, Ets-related gene (ERG), that mediates IL-9 production in TH9 cells in the absence of PU.1 and ETV5. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9 promoter region is restricted to the TH9 lineage and is sustained during murine TH9 polarization. Knockdown or knockout of ERG during murine or human TH9 polarization in vitro led to a decrease in IL-9 production in TH9 cells. Deletion of ERG in vivo had modest effects on IL-9 production in vitro or in vivo. However, in the absence of PU.1 and ETV5, ERG was required for residual IL-9 production in vitro and for IL-9 production by lung-derived CD4 T cells in a mouse model of chronic allergic airway disease. Thus, ERG contributes to IL-9 regulation in TH9 cells.
DNA damage resulting from cigarette smoke-induced oxidative stress activates the DDR signaling pathway, controlled mainly by the ATM (ataxia-telangiectasia mutated) protein kinase. The link between ...miR-126 and DDR signaling in COPD is currently unknown. ...we investigated whether miR-126 is reduced by cigarette smoke in vivo and in endothelial and lung epithelial cells from patients with COPD, as well as its link to DDR activation. ...miR-126 levels in lung epithelial cells negatively correlated with smoking history assessed as pack-years (Spearman's r = -0.73; P < 0.01) and positively correlated with disease severity measured as FEV1% predicted (Spearman's r = 0.57; P < 0.05), suggesting miR-126 expression is downregulated with extended exposure to cigarette smoke and increased severity of lung disease. Using a combined in vivo and ex vivo approach, namely, mice exposed to cigarette smoke and endothelial and lung epithelial cells from patients with COPD, we show that exposure to cigarette smoke downregulates miR-126 expression. miR-126 is critical for endothelial function, and miR-126 supplementation has been proposed therapeutically in in vivo models of vascular injury and pulmonary hypertension (5, 6).
Despite well-documented associations of socioeconomic status with incident heart failure (HF) hospitalization, little information exists on the relationship of socioeconomic status with HF diagnosed ...in the outpatient (OP) setting.
We used Poisson models to examine the association of area-level indicators of educational attainment, poverty, living situation, and density of primary care physicians with incident HF diagnosed in the inpatient (IP) and OP settings among a cohort of Medicare beneficiaries (n = 109,756; 2001–2013).
The age-standardized rate of HF incidence was 35.8 (95% confidence interval CI, 35.1–36.5) and 13.9 (95% CI, 13.5–14.4) cases per 1000 person-years in IP and OP settings, respectively. The incidence rate differences (IRDs) per 1000 person-years in both settings suggested greater incidence of HF in high- compared to low-poverty areas (IP IRD = 4.47 95% CI, 3.29–5.65, OP IRD = 1.41 95% CI, 0.61–2.22) and in low- compared to high-education areas (IP IRD = 3.73 95% CI, 2.63–4.82, OP IRD = 1.72 95% CI, 0.97–2.47).
Our results highlight the role of area-level social determinants of health in the incidence of HF in both the IP and OP settings. These findings may have implications for HF prevention policies.
The large multimeric glycoprotein Von Willebrand factor (VWF) is best known for its role in haemostasis; however in recent years other functions of VWF have been identified, indicating that this ...protein is involved in multiple vascular processes. We recently described a new role for VWF in controlling angiogenesis, which may have significant clinical implications for patients with Von Willebrand disease (VWD), a genetic or acquired condition caused by the deficiency or dysfunction of VWF. VWD can be associated with angiodysplasia, a condition of degenerative blood vessels often present in the gastrointestinal tract, linked to dysregulated angiogenesis. Angiodysplasia can cause severe intractable bleeding, often refractory to conventional VWD treatments. In this review we summarise the evidence showing that VWF controls angiogenesis, and review the angiogenic pathways which have been implicated in this process. We discuss the possible mechanisms though which VWF regulates angiopoietin-2 (Ang-2) and integrin αvβ3, leading to signalling through vascular endothelial growth factor receptor-2 (VEGFR2), one of the most potent activators of angiogenesis. We also review the evidence that links VWF with angiodysplasia, and how the newly identified function of VWF in controlling angiogenesis may pave the way for the development of novel therapies for the treatment of angiodysplasia in congenital VWD and in acquired conditions such as Heyde syndrome.
Coronary microvascular disease (CMD) and its progression towards major adverse coronary events pose a significant health challenge. Accurate in vitro investigation of CMD requires a robust cell model ...that faithfully represents the cells within the cardiac microvasculature. Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) offer great potential; however, they are traditionally derived via differentiation protocols that are not readily scalable and are not specified towards the microvasculature. Here, we report the development and comprehensive characterisation of a scalable 3D protocol enabling the generation of phenotypically stable cardiac hPSC-microvascular-like ECs (hPSC-CMVECs) and cardiac pericyte-like cells. These were derived by growing vascular organoids within 3D stirred tank bioreactors and subjecting the emerging 3D hPSC-ECs to high-concentration VEGF-A treatment (3DV). Not only did this promote phenotypic stability of the 3DV hPSC-ECs; single cell-RNA sequencing (scRNA-seq) revealed the pronounced expression of cardiac endothelial- and microvascular-associated genes. Further, the generated mural cells attained from the vascular organoid exhibited markers characteristic of cardiac pericytes. Thus, we present a suitable cell model for investigating the cardiac microvasculature as well as the endothelial-dependent and -independent mechanisms of CMD. Moreover, owing to their phenotypic stability, cardiac specificity, and high angiogenic potential, the cells described within would also be well suited for cardiac tissue engineering applications.
In this study, we report static and perfused models of human myocardial-microvascular interaction. In static culture, we observe distinct regulation of electrophysiology of human induced pluripotent ...stem cell derived-cardiomyocytes (hiPSC-CMs) in co-culture with human cardiac microvascular endothelial cells (hCMVECs) and human left ventricular fibroblasts (hLVFBs), including modification of beating rate, action potential, calcium handling, and pro-arrhythmic substrate. Within a heart-on-a-chip model, we subject this three-dimensional (3D) co-culture to microfluidic perfusion and vasculogenic growth factors to induce spontaneous assembly of perfusable myocardial microvasculature. Live imaging of red blood cells within myocardial microvasculature reveals pulsatile flow generated by beating hiPSC-CMs. This study therefore demonstrates a functionally vascularized in vitro model of human myocardium with widespread potential applications in basic and translational research.
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•Generation of perfusable microvasculature embedded in beating human myocardium•Distinct roles for endothelial cells and fibroblasts regulation of e-c coupling•Simultaneous quantification of contractility and intra-microvascular RBC velocity
In vivo, capillaries communicate with beating myocardium to regulate heart homeostasis, with disruption of communication between microvascular endothelial cells (MVECs) and cardiomyocytes (CMs) causing transition from healthy to disease phenotype. However, much remains unknown about the molecular mechanisms related to CM-EC communication. This had led to a lack of treatment options for diseases in which the myocardial microvascular is compromised, such as cardiac microvascular dysfunction (CMD). Our understanding has been limited by a lack of in vitro models that recapitulate microvascular architectures and the contractile and hemodynamic biomechanics of the beating heart.
The microvasculature of the heart supplies nutrients required to maintain heartbeat. When these vessels can become dysfunctional, cardiac disease occurs. In this study, King et al. use human stem cells and organ-on-a-chip technology to reproduce these vessels. They then demonstrate regulation of essential aspects of heart function by microvasculature.
Linear and disturbed flow differentially regulate gene expression, with disturbed flow priming endothelial cells (ECs) for a proinflammatory, atheroprone expression profile and phenotype. Here, we ...investigated the role of the transmembrane protein neuropilin-1 (NRP1) in ECs exposed to flow using cultured ECs, mice with an endothelium-specific knockout of NRP1, and a mouse model of atherosclerosis. We demonstrated that NRP1 was a constituent of adherens junctions that interacted with VE-cadherin and promoted its association with p120 catenin, stabilizing adherens junctions and inducing cytoskeletal remodeling in alignment with the direction of flow. We also showed that NRP1 interacted with transforming growth factor-β (TGF-β) receptor II (TGFBR2) and reduced the plasma membrane localization of TGFBR2 and TGF-β signaling. NRP1 knockdown increased the abundance of proinflammatory cytokines and adhesion molecules, resulting in increased leukocyte rolling and atherosclerotic plaque size. These findings describe a role for NRP1 in promoting endothelial function and reveal a mechanism by which NRP1 reduction in ECs may contribute to vascular disease by modulating adherens junction signaling and promoting TGF-β signaling and inflammation.
The American Heart Association's "Simple 7" offers a practical public health conceptualization of cardiovascular health (CVH). CVH predicts incident cardiovascular disease (CVD) in younger ...populations, but has not been studied in a large, diverse population of aging postmenopausal women. The extent to which CVH predicts cancer in postmenopausal women is unknown.
Multivariable Cox regression estimated hazard ratios and 95% CIs for the association between CVH and incident CVD, any cancer, and cancer subtypes (lung, colorectal, and breast) among 161,809 Women's Health Initiative observational study and clinical trial participants followed from 1993 through 2010. Data were analyzed in 2013. CVH score was characterized as the number (0 worst to 7 best) of the American Heart Association's ideal CVH behaviors and factors at baseline: smoking, BMI, physical activity, diet, total cholesterol, blood pressure, and fasting glucose.
Median follow-up was approximately 13 years. Fewer minorities and less educated women achieved ideal CVH, a common benchmark. In adjusted models, compared with women with the highest (best) CVH scores, those with the lowest (worst) CVH scores had nearly seven times the hazard of incident CVD (6.83, 95% CI=5.83, 8.00) and 52% greater risk of incident cancer (1.52, 95% CI=1.35, 1.72). Ideal CVH was most strongly inversely associated with lung cancer, then colorectal cancer, and then breast cancer.
Lower ideal CVH is more common among minority and less educated postmenopausal women and predicts increased risk of CVD and cancer in this population, emphasizing the importance of prevention efforts among vulnerable older adults.
Fluid shear stress in the vasculature is the driving force for natural bypass growth, a fundamental endogenous mechanism to counteract the detrimental consequences of vascular occlusive disease, such ...as stroke or myocardial infarction. This process, referred to as “arteriogenesis,” relies on local recruitment of leukocytes, which supply growth factors to preexisting collateral arterioles enabling them to grow. Although several mechanosensing proteins have been identified, the series of mechanotransduction events resulting in local leukocyte recruitment is not understood. In a mouse model of arteriogenesis (femoral artery ligation), we found that endothelial cells release RNA in response to increased fluid shear stress and that administration of RNase inhibitor blocking plasma RNases improved perfusion recovery. In contrast, treatment with bovine pancreatic RNase A or human recombinant RNase1 interfered with leukocyte recruitment and collateral artery growth. Our results indicated that extracellular RNA (eRNA) regulated leukocyte recruitment by engaging vascular endothelial growth factor receptor 2 (VEGFR2), which was confirmed by intravital microscopic studies in a murine cremaster model of inflammation. Moreover, we found that release of von Willebrand factor (VWF) as a result of shear stress is dependent on VEGFR2. Blocking VEGFR2, RNase application, or VWF deficiency interfered with platelet–neutrophil aggregate formation, which is essential for initiating the inflammatory process in arteriogenesis. Taken together, the results show that eRNA is released from endothelial cells in response to shear stress. We demonstrate this extracellular nucleic acid as a critical mediator of mechanotransduction by inducing the liberation of VWF, thereby initiating the multistep inflammatory process responsible for arteriogenesis.
•Shear stress–induced release of RNA from endothelial cells is crucial for initiation of arteriogenesis by controlling mechanotransduction.•Extracellular RNA is essential for VWF release from endothelial cells initiating the inflammatory process driving arteriogenesis.
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