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PubMed2025

Real-World Experience of Midodrine in Hospital Setting in Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH), a progressive disease, is characterized by increased pulmonary vascular resistance (PVR) and leads to right ventricular failure and premature death. PAH therapies aim to reduce PVR; however, these treatments as vasodilators may also result in reduced systemic vascular resistance and mean arterial pressure (MAP), leading to clinical or symptomatic hypotension. Low MAP can limit the administration of optimal dosage of PAH drugs. Midodrine, an oral alpha-1 adrenergic agonist, as a promising intervention, can potentially increase mean MAP and improve tolerance to PAH therapies. RESEARCH QUESTION: Does the use of midodrine improve MAP and allow for simultaneous uptitration of PAH therapy while hospitalized? STUDY DESIGN AND METHODS: A retrospective analysis of 433 patients treated at Houston Methodist Lung Center was undertaken between January 2005 and September 2022. Of these, 57 patients were prescribed midodrine during their hospital stay. We matched 57 patients 1:1 with propensity score matching between patients with PAH not given midodrine (control patients) based on age, sex, World Health Organization functional class, B-type natriuretic peptide, and 6-minute walk distance. RESULTS: Among hospitalized patients with PAH, those receiving midodrine were more likely to undergo uptitration of their PAH medications compared with those not receiving midodrine (n = 30 vs n = 17, respectively; P < .05). Patients on midodrine during hospitalization received higher doses of epoprostenol (P < .001), treprostinil (P < .05), and selexipag (P < .05). Additionally, no adverse effects attributable to midodrine were reported. INTERPRETATION: This study, to our knowledge the first large-scale analysis of PAH data, investigated the use of midodrine in hospitalized patients with PAH. In this single-center study, we share real-world experience of using midodrine to mitigate systemic hypotension, thereby facilitating the uptitration of PAH-targeted therapies.

B-type natriuretic peptide (BNP)↗

PubMed2026

GPER and EGFR cross-talk highlight aldosterone- and MR antagonist-induced NO production in cultured endothelial cells.

INTRODUCTION: Aldosterone induces rapid, non-genomic vasodilation of the rat mesenteric vasculature, and mineralocorticoid receptor (MR) antagonists are widely used in cardiovascular disease, yet their pharmacological profiles beyond classical MR blockade remain unclear. We examined whether the G protein-coupled estrogen receptor (GPER/GPR30), functionally coupled to the epidermal growth factor receptor (EGFR), accounts for the rapid endothelial nitric oxide (NO) component of aldosterone action, and whether MR antagonists display intrinsic GPER-linked activity. METHODS: Aldosterone-induced vasodilation was assessed in isolated perfused rat mesenteric arterial beds precontracted with noradrenaline, and NO production was quantified in primary mesenteric endothelial cell cultures by DAF-FM fluorescence with validated vehicle controls. The mechanisms engaged by spironolactone, eplerenone and finerenone were interrogated with selective pharmacological tools and by endothelium removal. Ligand recognition was explored by molecular docking in a comparative model of the rat GPER built on the human GPER cryo-EM template. RESULTS: Aldosterone elicited concentration-dependent endothelial NO production (EC50 = 2.26 ± 0.3 nM) and vasodilation (EC50 = 0.9 ± 0.2 nM) that were closely correlated (R2 = 0.969, p < 0.01). All three MR antagonists blocked the aldosterone responses, yet each also evoked intrinsic, concentration-dependent NO production in the absence of aldosterone, eplerenone and spironolactone showing greater intrinsic efficacy than finerenone. Pretreatment with 100 nM of the GPER antagonist G-36 or 100 nM AG-1478 significantly reduced both aldosterone-induced DAF-NO signaling and vasodilation, whereas endothelium removal or L-NAME converted vasodilation into vasoconstriction. Aldosterone signaling additionally required PI3K, PKA and IP3 receptor-gated Ca2+ mobilization. Docking identified plausible receptor-engaging poses, with steroidal ligands converging on a shared cavity and finerenone adopting a distinct binding mode. DISCUSSION: MR antagonists elicit endothelial NO production through a G-36-sensitive, GPER-linked pathway functionally coupled to EGFR signaling, rather than acting as pure competitive antagonists in this context. Because recent cryo-EM work reveals a non-canonical extracellular GPER architecture, the docking results are interpreted as structurally plausible interaction scenarios rather than definitive orthosteric assignments; whether the behaviour reflects direct partial agonism at GPER or an indirect, GPER-dependent mechanism remains to be established by direct-binding studies. These findings expand current understanding of MR antagonist pharmacology.

GPER/GPR30↗

PubMed2025

Identification of two biological subgroups of complex regional pain syndrome type 1 by transcriptomic profiling of skin and blood in women.

BACKGROUND: Patients with Complex Regional Pain Syndrome (CRPS) present prolonged, debilitating pain and functional impairment. Treatments are not disease-modifying due to the poorly understood underlying pathomechanisms. This study aimed to identify the molecular signatures of potential CRPS type 1 subgroups. METHODS: Twelve women with CRPS type 1 were included. Demographics and pain questionnaires were recorded. Skin biopsies of the affected and non-affected limbs (n = 6 + 6) and peripheral blood (n = 11) were collected. RNA sequencing was performed on skin and peripheral blood mononuclear cells (PBMCs). Twenty cytokines were quantified in blood plasma (n = 12). RESULTS: Cluster analysis of the affected skin identified two CRPS subgroups (SG). SG1 exhibited increased gene expression related to epidermal development, metabolic processes, and a greater abundance of keratinocytes. SG2 showed enhanced transcriptomic changes in inflammatory, immune, and fibrotic processes, along with higher abundance of fibroblasts, macrophages, and endothelial cells. PBMCs transcriptomics revealed the same SG1/SG2 clusters and highlighted a stronger inflammatory response in the blood of SG1, suggesting distinct tissue-specific immune responses for the subgroups. Interleukin-1 receptor antagonist (IL-1RA) levels were higher in the blood plasma of SG1 (FDR = 0.01), consistent with its encoding gene IL1RN expression in PBMCs (log2 FC = 1.10, P < 0.001) and affected skin (log2 FC = 0.88, P = 0.006). Subgroups did not differ in demographic or clinical parameters but correlations among clinical factors varied between them. CONCLUSIONS: This study identified two potential biological subgroups of CRPS type 1 in women through skin and blood transcriptomic profiling, advancing the understanding of this condition. This could facilitate the development of targeted treatments for CRPS type 1.

Humans↗

PubMed2026

Lipid-mediated activation of BLT2 promotes membrane repair to prevent cell death.

Various pathogenic microorganisms produce toxins that create pores in cell membranes, causing cell damage and disrupting the host epithelial barrier. Recently, we reported that mice lacking the G protein-coupled receptor leukotriene B4 receptor 2 (BLT2), which is expressed in vascular endothelial and alveolar epithelial cells, are highly susceptible to pneumolysin (PLY), a pneumococci-generated toxin. Although we clarified the protective roles of BLT2 in vascular endothelial cells, those in alveolar epithelial cells have not been elucidated. Here, we report that lipid mediator 12-hydroxyheptadecatrienoic acid (12-HHT), which is produced by membrane-damaged epithelial cells, prevents cell death by promoting membrane repair through BLT2. BLT2 promoted the release of PLY-bound plasma membranes as extracellular vesicles in a sphingomyelinase-dependent manner. Additionally, BLT2 activated Rac1 and subsequent actin polymerization, leading to resistance to cell death. Furthermore, inhibition of 12-HHT production by aspirin and treatment with a BLT2 antagonist abolished the protective effect of BLT2. These findings provide a new therapeutic strategy for bacterial infection.

Receptors, Leukotriene B4↗

PubMed2026

Comparison of endothelin-1 levels in plasma from human coronary arteries measured by enzyme linked immunosorbent assay and Olink high-throughput proteomics platform.

Endothelin-1 (ET-1) antagonists are increasingly being approved for new treatments for cardiovascular disease, where elevated ET-1 levels contribute to increased vasoconstriction. Further therapeutic targets, including coronary artery disease, are under investigation. The Olink Explore 3072 Proximity Extension Assay platform enables multiplexed high-throughput measurement of ~3000 plasma proteins, from minimal (≤6 µL) sample volumes. However, it is not known if the two oligonucleotide-tagged antibodies raised against preproET-11-212, used in this Olink assay, specifically measure biologically active ET-1 or the other inactive EDN1-encoded peptides, also secreted by human endothelial cells. Paired plasma samples from 29 patients with coronary artery disease were obtained, using a specialised intra-coronary sampling catheter, designed to obtain site specific biochemical information from within coronary arteries. We compared ET-1 concentrations measured with an ET-1 specific ELISA, demonstrated to have no cross-reactivity with other EDN1-encoded peptides versus values obtained using Olink Explore platform. Olink-measured ET-1 correlated significantly with ELISA-derived ET-1 levels (r = 0.53, p = 0.003), and Olink values predicted ELISA results. Olink ET-1 concentrations also correlated with ETB receptor levels (r = 0.40, p < 0.05). These findings indicate that the Olink Explore platform can detect relative changes in biologically active ET-1, supporting its use as a biomarker tool in clinical and translational studies.

Humans↗