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Supplementation with the gut microbial-derived metabolites acetate and butyrate has been shown to lower blood pressure in experimental models of hypertension. However, the translational potential of these metabolites has been unexplored. We provide clinical evidence that acetate and butyrate lower blood pressure in untreated patients with hypertension.
Endothelial cell–cell contacts in blood vessels constitute a barrier to the flux of molecules and cells from blood to tissues. We identified the tyrosine-protein kinase Yes as the principal regulator of collective endothelial cell migration and vascular barrier dynamics, a finding that opens avenues for future therapeutic development.
Postural orthostatic tachycardia syndrome (POTS) has been observed following SARS-CoV-2 infection. In this study, we observed occurences of POTS following COVID-19 vaccination, albeit at a lower rate than following COVID-19 infection.
Clustering the atherosclerotic plaques of patients based on gene expression unearths novel and clinically relevant heterogeneity beyond the established dogma of ‘stable’ and ‘unstable’ plaques.
The mechanisms of adrenergic stimulation of cardiac voltage-gated calcium (CaV) channels have remained elusive. Using proximity proteomics and genetically altered mice, we show that phosphorylation of the CaV channel inhibitor Rad is essential for regulation, by the sympathetic nervous system, of calcium influx, and for augmentation of cardiac contractility.
Loss of VEGF-C or VEGFR3 function or gain of VE-cadherin function causes identical defects in sinusoidal and lymphatic growth, resulting in anemia and lymphedema. Mechanistically, VEGF-C drives VE-cadherin phosphorylation and endocytosis whereas VE-cadherin prevents VEGFR3 internalization and downstream growth factor signaling. In the absence of VEGFR3, reducing VE-cadherin levels rescues vascular growth by potentiating VEGF-C–VEGFR2 signaling.
GPR55 is a G protein–coupled receptor that is activated by endogenous lipid mediators. Our findings in experimental mouse models of atherosclerosis and human plaques indicate that GRP55 signaling is important for limiting B cell activation and humoral responses during hypercholesterolemia, which suggests that GPR55 signaling has an atheroprotective role.
Myocardial ischemia–reperfusion injury (MIRI) substantially contributes to the morbidity associated with ischemic heart disease. Timed administration of digoxin decreased the susceptibility of mouse cardiomyocytes to MIRI; digoxin acted by promoting proteasomal degradation of the nuclear receptor REV-ERBα, a key component of the molecular circadian clock.
Little is known about the maintenance of endothelial cell fate in adults. We show that deletion of Erg and Fli1 in endothelial cells of adult mice causes loss of endothelial cell fate and vascular collapse. Overexpression of ERG and FLI1 in non-vascular cells activates an endothelial cell program, confirming their regulation of endothelial cell identity.
We explored age-dependent patterns in sex differences for a wide range of cardiometabolic disease risk factors and observed widespread and divergent patterns for different risk-factor groups. These findings highlight the importance of taking both age and sex into account when assessing a person’s risk of developing cardiometabolic disease.
Heart failure is marked by metabolic insufficiency, but detailed understanding of the underlying metabolic rewiring has been limited. By applying state-of-the-art mass spectrometry to a large pool of human hearts in end-stage heart failure, we unveil numerous metabolic aberrations in human heart failure.
LTBP-2 expression is increased in the right ventricle and plasma of patients with pulmonary arterial hypertension. Circulating levels of LTBP-2 correlate with right ventricular function and predict long-term survival in two independent cohorts of patients with pulmonary arterial hypertension.
Sepsis-derived S100A8/A9 induces GSDMD-dependent platelet pyroptosis via the TLR4–ROS–NLRP3–caspase 1 pathway, leading to the release of oxidized mitochondrial DNA that contributes to the formation of neutrophil extracellular traps (NETs). NETs in turn release S100A8/A9 and accelerate platelet pyroptosis, forming a positive feedback loop and thereby amplifying the production of proinflammatory cytokines.
In patients with coronary artery disease, stabilizing post-translational modifications to the mRNA of the immune-checkpoint inhibitor CD155 result in an immunosuppressive macrophage phenotype and impair activation of T cells in response to viral infection.
In lung tissues of pulmonary hypertension rodent models, B cell activation and immunoglobulin E (IgE) production lead to mast cell activation and release of the cytokines IL-6 and IL-13, which result in remodeling of vascular smooth muscle cells. Blockade of IgE with omalizumab, a clinically approved monoclonal antibody against IgE, alleviated the progression of experimental pulmonary hypertension.
In a prospective experimental observational study of 18 individuals with severe, recurrent extracranial arteriovenous malformations, thalidomide was effective in reducing pain, healing ulceration, stopping bleeding and resolving cardiac failure.
Elucidation of the mechanisms that drive tumor resistance to anti-angiogenic therapies is expected to improve treatment options. This report shows that endothelial apelin signaling promotes the migration of distant venous endothelial cells toward the tumor progenitor cell niche to support vessel expansion and sustain a normoxic microenvironment, and that it does so independently of vascular endothelial growth factor A.
Fibroblast growth factor homologous factors (FHFs) are an auxiliary subunit of the cardiac voltage-gated sodium channel. We found that FHFs can inhibit the arrhythmogenic late sodium current (INa,L) in an isoform-specific manner, and engineered an FHF-based cell-penetrating peptide that acts as an inhibitor of INa,L and opens avenues for developing future therapeutics.
Using a quantitative statistical approach, we created a 3D atlas of embryonic cardiac morphogenesis from a collection of mouse specimens. The atlas includes the average shape of tissue geometry over time and its range of variability, and it enabled us to identify the onset of cardiac left–right asymmetry.
In mouse models of atherosclerosis, smooth muscle cell (SMC)-specific disruption of a gene associated with coronary artery disease in human genome-wide association studies alters atherosclerotic plaque features by promoting SMC transition to an atherogenic phenotype.