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Heart failure is a leading cause of morbidity and mortality 1 , 2 . Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion 3 – 8 . Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect 9 , 10 . Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure. Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

MicroRNAs (miRNAs) are a key factor in epigenetic regulation of gene expression, but miRNA responses to fine particulate matter (PM ) air pollution and their potential contribution to cardiovascular effects of PM are unknown. We explored the potential influence of PM on the expression of selected cytokines relevant to systemic inflammation, coagulation, and vasoconstriction, and on miRNAs that may regulate their expression. We designed a double-blind, randomized crossover study in which true and sham air purifiers were used to expose 55 healthy young adult students in Shanghai, China, to reduced or ambient levels of indoor PM during two-week periods, and we measured the expression (mRNA and protein) of 10 serum cytokines, and miRNAs that target them, after each intervention period. We used linear mixed-effect models to estimate associations of the intervention, and time-weighted personal PM exposures, with the cytokines, mRNA, and miRNAs; we also explored potential mediation by miRNAs. The findings were generally consistent for associations with the intervention and for associations with an interquartile range increase in time-weighted PM . Specifically, higher PM exposure was positively associated with the expression (mRNA, protein, or both) of interleukin-1 (encoded by ), IL6, tumor necrosis factor (encoded by ), toll-like receptor 2 (encoded by ), coagulation factor 3 (encoded by ), and endothelin 1 (encoded by ), and was negatively associated with miRNAs (miR-21-5p, miR-187-3p, miR-146a-5p, miR-1-3p, and miR-199a-5p) predicted to target mRNAs of , , , and . Our findings require confirmation but suggest that effects of PM on cardiovascular diseases may be related to acute effects on cytokine expression, which may be partly mediated through effects of PM on miRNAs that regulate cytokine expression. https://doi.org/10.1289/EHP1447.

Rivaroxaban (RVX) was suggested to possess anti-inflammatory and vascular tone modulatory effects. The goal of this study was to investigate whether RVX impacts lipopolysaccharide (LPS)-induced acute vascular inflammatory response. Male rats were treated with 5 mg/kg RVX (oral gavage) followed by 10 mg/kg LPS i.p injection. Circulating levels of IL-6, MCP-1, VCAM-1, and ICAM-1 were measured in plasma 6 and 24 hours after LPS injection, while isolated aorta was used for gene expression analysis, immunohistochemistry, and vascular tone evaluation. RVX pre-treatment significantly reduced LPS mediated increase after 6h and 24h for IL-6 (4.4±2.2 and 2.8±1.7 fold), MCP-1 (1.4±1.5 and 1.3±1.4 fold) VCAM-1 (1.8±2.0 and 1.7±2.1 fold). A similar trend was observed in the aorta for iNOS (5.5±3.3 and 3.3±1.9 folds reduction, P<0.01 and P<0.001, respectively), VCAM-1 (1.3±1.2 and 1.4±1.3 fold reduction, P<0.05), and MCP-1 (3.9±2.2 and 1.9±1.6 fold reduction, P<0.01). Moreover, RVX pre-treatment, improved LPS-induced PE contractile dysfunction in aortic rings (Control vs LPS, Emax reduction = 35.4 and 31.19%, P<0.001; Control vs LPS+RVX, Emax reduction = 10.83 and 11.48%, P>0.05, respectively), resulting in 24.5% and 19.7% change in maximal constriction in LPS and LPS+RVX respectively. These data indicate that RVX pre-treatment attenuates LPS-induced acute vascular inflammation and contractile dysfunction.

Background/Objective Reversible cerebral vasoconstriction syndrome may be underdiagnosed. It can be accompanied by various complications, mainly intracerebral hemorrhage and ischemic stroke. The clinical presentation of this condition varies according to its localization. The aims of this review are to raise awareness of the disease, especially in the presence of corresponding risk factors; to connect its precipitating factors, pathophysiology, and complications; and to compare various differential diagnoses of vasoconstriction. Methods A review of the literature in PubMed/MEDLINE and Google Scholar was conducted from May 1997 until May 2022. Results Reversible cerebral vasoconstriction syndrome, which is a clinical–radiological syndrome, is mainly characterized by the occurrence of thunderclap headache and widespread vasoconstriction. The most common precipitating factors are the use of vasoactive substances and postpartum status. The pathophysiology is currently assumed to include two mechanisms: sympathetic overactivity and endothelial dysfunction. From these mechanisms, it is possible to derive potential complications as well as the most important differential diagnoses: posterior reversible encephalopathy syndrome, convexity subarachnoid hemorrhage, ischemic and hemorrhagic stroke, and primary angiitis of the central nervous system. Conclusion In general, the outcome of reversible cerebral vasoconstriction syndrome is very good. Vasospasm as well as thunderclap headache attacks can be fully reversible, and > 90% of patients are functionally independent at discharge.

Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange but, when impaired, can result in life-threatening hypoxemia. Moreover, under conditions of generalized alveolar hypoxia, HPV can result in pulmonary hypertension. Voltage-gated K[sup.+] channels (K[sub.v] channels) are key to HPV: a change in the intracellular hydrogen peroxide (H[sub.2]O[sub.2]) levels during acute hypoxia is assumed to modulate these channels’ activity to trigger HPV. However, there are longstanding conflicting findings on whether H[sub.2]O[sub.2] inhibits or activates K[sub.v] channels. Therefore, we hypothesized that H[sub.2]O[sub.2] affects K[sub.v] channels depending on the experimental conditions, i.e., the H[sub.2]O[sub.2] concentration, the channel’s subunit configuration or the experimental clamping potential in electrophysiological recordings. Therefore, cRNAs encoding the K[sub.v]1.5 channel and the auxiliary K[sub.v]β subunits (K[sub.v]β1.1, K[sub.v]β1.4) were generated via in vitro transcription before being injected into Xenopus laevis oocytes for heterologous expression. The K[sup.+] currents of homomeric (Kv1.5) or heteromeric (K[sub.v]1.5/K[sub.v]β1.1 or K[sub.v]1.5/K[sub.v]β1.4) channels were assessed by two-electrode voltage clamp. The response of the K[sub.v] channels to H[sub.2]O[sub.2] was markedly dependent on (a) the clamping potential, (b) the H[sub.2]O[sub.2] concentration, and (c) the K[sub.v] channel’s subunit composition. In conclusion, our data highlight the importance of the choice of experimental conditions when assessing the H[sub.2]O[sub.2] sensitivity of K[sub.v] channels in the context of HPV, thus providing an explanation for the long-lasting controversial findings reported in the literature.

Background The diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) is challenging due to its varied clinical manifestations and imaging findings. While it typically presents with a sudden, severe thunderclap headache and multifocal constriction of the cerebral arteries, the wide spectrum of radiological presentations may complicate the diagnosis. Main Body This review presents a series of cases that show both typical and atypical presentations of RCVS. Typical cases show the characteristic “string of beads” pattern on angiography, which usually resolves within 3–6 months. However, diagnostic challenges arise when angiography appears normal in the early stages or when imaging artifacts obscure the findings. In addition, the variability in vasoconstriction patterns and the need for a differential diagnosis further complicate the accurate identification. These cases highlight the importance of considering RCVS in patients with recurrent thunderclap headaches, even when the initial imaging is inconclusive. Recognizing these challenges and the variability in presentation, along with the use of high-resolution vessel wall MRI and blood-brain barrier imaging, can improve diagnostic accuracy and improve patient outcomes. Conclusion The diagnosis of RCVS requires careful integration of clinical evaluation and advanced imaging techniques, with particular attention to radiological findings that can guide accurate diagnosis and management. Despite challenges, such as normal early stage angiography and imaging variability, maintaining a high suspicion of RCVS is essential, especially in patients with recurrent thunderclap headaches.

Sympathetic hyperactivity and relative NO deficiency are characteristic alterations in both genetic and salt hypertension. The contribution of these abnormalities to blood pressure (BP) maintenance can be determined in conscious rats using a consecutive blockade of particular vasoactive systems. Thus, the contribution of pressor effects of angiotensin II to the maintenance of high BP is usually small, but the role of renin-angiotensin system in the development of hypertension mediated by central and peripheral effects of angiotensin II on sympathetic activity is highly important. This is even true in angiotensin-dependent hypertension of heterozygous Ren-2 transgenic rats in which sympathetic hyperactivity is increasing with age. Central sympathoexcitation in this hypertensive model can be inhibited by lower losartan doses than peripheral angiotensin II-dependent vasoconstriction. This experimental model also yielded important knowledge on nephroprotective effects of new therapeutic drugs - endothelin receptor type A blockers. A considerable part of sympathetic vasoconstriction is dependent on the interaction of Ca2+ sensitization (RhoA/Rho kinase pathway) and Ca2+ influx (through L-VDCC). The blockade of these pathways prevents a major part of sympathetic vasoconstriction. Ca2+ sensitization seems to be attenuated in genetic hypertension in order to compensate increased Ca2+ influx. In contrast, enhanced Ca2+ sensitization is a hallmark of salt sensitivity in Dahl rats in which salt hypertension is dependent on increased Ca2+ influx. The attention should also be paid to the impairment of arterial baroreflex sensitivity which permits enhanced BP responses to pressor or depressor stimuli. Some abnormalities can be studied in blood vessels isolated from hypertensive rats but neither conduit arteries nor mesenteric resistance arteries represent the vascular beds decisive for the increased peripheral resistance and high BP.

Mammalian biology adapts to physical activity but the molecular mechanisms sensing the activity remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force to enable vascular development. Here, we address Piezo1 in adult endothelium, the major control site in physical activity. Mice without endothelial Piezo1 lack obvious phenotype but close inspection reveals a specific effect on endothelium-dependent relaxation in mesenteric resistance artery. Strikingly, the Piezo1 is required for elevated blood pressure during whole body physical activity but not blood pressure during inactivity. Piezo1 is responsible for flow-sensitive non-inactivating non-selective cationic channels which depolarize the membrane potential. As fluid flow increases, depolarization increases to activate voltage-gated Ca 2+ channels in the adjacent vascular smooth muscle cells, causing vasoconstriction. Physical performance is compromised in mice which lack endothelial Piezo1 and there is weight loss after sustained activity. The data suggest that Piezo1 channels sense physical activity to advantageously reset vascular control. The mechanisms that regulate the body’s response to exercise are poorly understood. Here, Rode et al. show that the mechanically activated cation channel Piezo1 is a molecular sensor of physical exercise in the endothelium that triggers endothelial communication to mesenteric vessel muscle cells, leading to vasoconstriction.

Background and purpose Up to 80% of patients diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) experience complications such as ischaemic stroke, intracerebral or subarachnoid haemorrhage or posterior reversible encephalopathy syndrome. The aim was to evaluate the incidence of complications in patients diagnosed with RCVS in our clinic. Patients and methods All adult patients (age >16 years) diagnosed with RCVS at the Helsinki University Central Hospital during the period between 1 January 2016 and 31 December 2022 were retrospectively identified. Medical and follow‐up data were collected from medical records. Results Eighty patients diagnosed with RCVS were identified, of whom four patients had parenchymal lesions such as ischaemic stroke, intracerebral haemorrhage, posterior cerebral encephalopathy syndrome, subarachnoid haemorrhage or combinations thereof. Conclusion The complication rate of RCVS is lower than in previously published cohorts. This may be related to better and earlier diagnostics and earlier withdrawal of possible triggers.