Cardiovascular and metabolic diseases pose a significant challenge to healthcare globally. Current theories for the pathology of these diseases involve dysfunctional interactions between lipid-droplets and mitochondria leading to improper energy consumption or storage. Research is currently limited by technique, mitochondrial tracking stains are limited for use in living cells which reduces the variety of possible research. This research sought to design a new method that would combine the use of Oil red O lipid droplet staining and mitochondrial staining with MitoBrilliant 646 in OCT fixed patient heart tissue. This method allowed characterisation of how lipid droplets and mitochondria can be visualised in tissue to assess if factors such as body mass index (BMI) and age contribute to dysfunctional interactions. Demonstrating that mitochondrial fluorescent stains are viable for used in OCT fixed tissue and provides new options for scientific research into mitochondria.

Subcutaneous adipose tissue microvascular endothelial cells (MVECs) from patients with type 2 diabetes mellitus and heart failure exhibit a senescent phenotype characterized by elevated senescence-associated secretory phenotype markers, reduced adenosine triphosphate production, and impaired angiogenic and proliferative capacities. When cocultured with healthy adipocytes, senescent MVECs drive adverse cross-talk, inducing a proinflammatory adipocyte phenotype with increased interleukin-6 expression and reduced glucose uptake. Digoxin reduces MVEC senescence and restores healthy cross-talk, improving glucose uptake and mitigating the effects of senescent MVECs on adipocytes.

The idea of myocardial mechanical reflexes was previously considered, but it struggled to gain traction in mainstream thinking. New research shows PIEZO2 ion channels conferring vagal force sensing in atrial and ventricular myocardium to protect the circulation as blood volume changes with gravity and injury.

TRPC4/5 cation channels are polymodal cellular sensors and emerging drug targets in various human pathologies. The plant natural product (-)-englerin A (EA) is a potent, selective TRPC4/5 agonist that has transformed TRPC4/5 research. However, the structural basis of EA-mediated TRPC4/5 activation has remained elusive, limiting our ability to understand and exploit EA's pharmacology. Here, we present nine high-resolution cryo-EM structures of human TRPC5, representing different states and ligand occupancies, which show that EA occupies a conserved lipid binding site between channel subunits. Conformational changes of residues surrounding this binding site - most notably in the aromatic interaction network around Phe520 - result in rearrangement of the pore helices into a pre-open state. Our structural models are consistent with the effects of mutagenesis on EA's potency, efficacy and activation kinetics, and allow us to rationalise competitive inhibition by other TRPC4/5 modulators as well as EA's selectivity profile within the TRPC family. Our structural insights into the mode-of-action of a widely used TRPC4/5 agonist will underpin fundamental TRPC4/5 research and ongoing drug discovery programmes.

Abstract Exercise orchestrates an interorgan communication network, in which skeletal muscle releases signaling molecules known as myokines that contribute to exercise training-induced adaptations. We identified the muscle-derived metabolite beta-aminoisobutyric acid (BAIBA) as a regulator of adipose and hepatic metabolic responses to exercise. Here, we demonstrate that BAIBA regulates muscle metabolism, morphology and function via peroxisome proliferator-activated receptor delta (PPARδ) to determine exercise performance in mice. BAIBA mitigates muscle dysfunction in a mouse model of diabetes. Physiologically, BAIBA exists as D- and L- enantiomers. We identify L-BAIBA as the primary mediator of muscular effects. Knockdown of L-BAIBA’s biosynthetic enzyme, 4-aminobutyrate aminotransferase, in mouse hindlimb muscle impairs exercise-induced adaptations and performance gains. L-BAIBA regulates human myotube fibertype and differentiation markers through Mas-related G-protein coupled receptor D. In humans, plasma L-BAIBA correlates with aerobic fitness and increases with endurance exercise training. BAIBA acts through the PGC1α-BAIBA-PPARδ axis to facilitate muscle adaptation and exercise performance.

The PIEZO1 and PIEZO2 membrane proteins form uniquely structured calcium permeable nonselective cation channels dedicated to mechanical force sensing in eukaryotic cells. In this review of the scientific literature, we address PIEZOs in the heart. PIEZOs enable the formation of the aortic valve, cardiac vasculature, and pericardial drainage. In the established heart, they enable baroreceptor pressure sensing and reflex regulation of the heart rate and influence the heart's size and stiffness through roles in cardiac myocytes and cardiac fibroblasts. Therefore, mechanical force sensing by PIEZOs participates in normal cardiac development and function. There is also interest in PIEZOs in pathophysiology, when the structure and mechanical properties of the heart often change. Studies in rats and mice suggest that experimentally induced cardiac stress and injury cause PIEZO upregulation that is adverse. Similar changes may occur in human heart disease, creating potential for therapeutic benefit through PIEZO modulation. This is a productive, accelerating, and exciting new research topic with importance for our understanding of the heart and its diseases.

BACKGROUND:Pathological remodelling of native vascular smooth muscle cells (VSMC) within the arterial wall is a key contributor to vascular disease. A driver of this remodelling is platelet-derived growth factor BB (PDGF-BB) and its signalling via activation of the store-operated calcium ion channel, ORAI1. Here, we investigated if there are associations of ORAI1 polymorphisms with human cardiovascular disease. METHODS AND RESULTS:We conducted candidate gene association analysis and revealed that a missense ORAI1 variant (rs3741596, S218G) associates with an increased risk of hospital-diagnosed peripheral vascular disease, generalised atherosclerosis, acute ischaemic heart disease, and atrioventricular and left bundle-branch block in White British UK Biobank participants. Rs3741596 is also associated with higher circulating platelet counts and reduced total triglyceride levels. Functional analysis of the effects of rs3741596 S218G variant on ORAI1 channel function, via introduction of the S218G ORAI1 variant in HEK293 cells using CRISPR/Cas9 and investigation of its effects on store-operated calcium entry (SOCE), showed significantly enhanced SOCE compared to wild type cells, suggesting that the S218G variant enhances ORAI1 function. CONCLUSIONS:Our results reveal an association between an ORAI1 missense variant and hospitalisation for peripheral vascular disease, generalised atherosclerosis, acute ischaemic heart disease, and atrioventricular and left bundle-branch block. These findings provide a novel insight into the role of ORAI1 in vascular remodelling and highlight its potential as a treatment target for vascular pathologies.

The physiological role of the Orai1 channel, a store-operated Ca2+ channel in adult ventricular cardiomyocytes, remains incompletely defined. Here, we report that Orai1 may contribute to excitation-contraction coupling (ECC) in a sex-specific manner. Using a mouse model with cardiac-specific expression of a dominant-negative human Orai1R91W mutant (C-dnO1), we found elevated Ca2+ transients and Ca2+ spark amplitudes in female C-dnO1 mice in comparison with littermate wild-type (WT) controls, but not in male mice. The Orai1 protein expression, cellular distribution, and store-operated Ca2+ entry activity were similar in WT males and females and equally diminished in both sexes with C-dnO1 expression. These findings reveal that chronic functional suppression of Orai1 abrogates sex differences in cardiomyocyte ECC, uncovering a novel mechanistic contribution of Orai1 to sexual dimorphism in cardiac function.NEW & NOTEWORTHY This short report reveals a novel mechanistic contribution of the Ca2+ channel Orai1 to sexual dimorphism in cardiac physiology. We demonstrated that the chronic functional suppression of Orai1 abrogates sex differences in cardiomyocyte excitation-contraction coupling.

The hepatobiliary system is constantly exposed to dynamic mechanical forces, including fluid shear stress, bile canaliculi pressure, and extracellular matrix stiffness. Although traditionally studied for its metabolic and detoxifying functions, it is now increasingly recognized as a mechanosensitive organ. This review focuses on PIEZO1 mechanically gated ion channels that transduce physical cues into calcium-dependent signaling events. PIEZO2, the only other PIEZO isoform, is not known to be relevant in the hepatobiliary system. We examine the current knowledge on PIEZO1 in liver physiology, highlighting its roles in liver sinusoidal endothelial cells, hepatocytes, and macrophages. In health, PIEZO1 regulates key processes such as bile acid synthesis (through nitric oxide-mediated suppression of CYP7A1), bile flow, antioxidant defense, and iron homeostasis. In disease, PIEZO1 activity is linked to pathological processes such as inflammation, fibrosis, and angiogenesis in the context of cirrhosis and hepatocellular carcinoma. We discuss the idea that the liver alternates between two functional states depending on portal vein flow: a high-flow state favoring detoxification and metabolism, and a low-flow state that prioritizes bile acid production. Understanding how PIEZO1 contributes to these transitions offers new insights into liver's ability to adapt its function and metabolism. Further research on hepatobiliary PIEZO1 will advance the understanding of how physical exercise promotes health and opens new opportunities for enhancing liver regeneration after surgical resection and liver function in chronic diseases such as fibrosis and cirrhosis.

Angiopoietin2 (Ang2), a regulator of angiogenesis, is stored with other pro-inflammatory and pro-thrombotic mediators, in endothelial-specific vesicles called Weibel-Palade bodies (WPBs). The WPB secretagogue, histamine, delays Ang2 secretion by activating Rab46-specific trafficking of Ang2-positive WPBs to the microtubule organising centre (MTOC), where they persist until Ca2+ binds to the EF-hand of Rab46, enabling detachment. Here, using Ca2+ imaging and high-resolution light microscopy, we pharmacologically investigated the contribution of endolysosomal two-pore channels proteins (TPC) to the Ca2+ signal necessary for Ang2 secretion. We show an increase in the histamine-evoked clustering of Rab46 (and thus WPBs) at the MTOC in the presence of TPC inhibitors Ned19 and tetrandrine, and a decrease in the presence of a TPC2 agonist, TPC2-A1-N. Histamine-evoked secretion of Ang2 was decreased by pharmacological inhibition of TPC channels but potentiated in the presence of an TPC2 agonist. These data suggest that histamine-mediated Ca2+ release via TPC2 channels is necessary for the Rab46-dependent detachment of Ang2-positive WPBs from the MTOC and thus Ang2 secretion. ### Competing Interest Statement The authors have declared no competing interest.

The large membrane protein PIEZO1 assembles as trimers to form exceptional mechanical force-sensing ion channels of eukaryotes. When these channels are activated by force, cell membrane permeability to calcium ions and other ions increases rapidly, coupling force to cell function through ionic control. In humans and other species, PIEZO1 is both widely expressed and functional across major systems that include the cardiovascular, haematological and musculoskeletal systems, thereby serving diverse needs. In this narrative review of the scientific literature, we address what has been learned about PIEZO1 from associations of its gene variation with human characteristics. A particular physiological importance of PIEZO1 is emerging in lymphatics and thus in the control of tissue fluid homeostasis with relevance to the disease conditions of non-immune fetal hydrops and generalized lymphatic dysplasia. Other vascular relevance is seen in lower limb venous varicosities. PIEZO1 may be non-essential in red blood cells but the amplification of its function by gene variation quite selectively alters these cells, leading to haemolytic anaemia and other related disturbances that may be only mildly adverse and confer survival advantage. We speculate on what else might be learned in humans, guided by knowledge from PIEZO1 studies in mice, and describe how knowledge accumulated to date highlights new opportunities for PIEZO1 understanding and pathways to patient benefit.

During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes. The endothelium has been suggested to act as a paracrine organ. We explore the role of endothelial insulin-like growth factor-1 receptor (IGF-1R), as a paracrine modulator of white adipose phenotype. We show that a reduction in endothelial IGF-1R expression in the presence of high-fat feeding in male mice leads to depot-specific beneficial white adipose tissue remodelling, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell-autonomous paracrine mechanism. We demonstrate that increased endothelial malonate may be contributory and that malonate prodrugs have potentially therapeutically relevant properties in the treatment of obesity-related metabolic disease.

TRPC4/5 cation channels are polymodal cellular sensors that play key roles in signal transduction/integration and have been implicated in various human pathologies, including anxiety, pain and cardiometabolic disease[1][1]–[3][2]. The plant natural product (-)-englerin A (EA)[4][3] is a potent, selective TRPC4/5 agonist[5][4],[6][5] that has transformed fundamental and translational research on TRPC4/5 channels. However, the structural basis of interactions between EA and TRPC4/5 proteins has remained elusive, limiting our ability to fully understand and exploit mechanisms of TRPC4/5 channel activation by this intriguing natural product. Here, we present nine high-resolution cryo-EM structures (2.4-3.2 Å) of human TRPC5 – representing different states and ligand occupancies – which show that EA binds to a conserved lipid binding site between transmembrane domains of adjacent TRPC5 subunits. Our structural models are consistent with the effects of mutagenesis of nearby residues on EA’s potency, efficacy and activation kinetics, and allow us to rationalise competitive inhibition by other TRPC4/5 modulators as well as EA’s selectivity profile within the TRPC family. Comparison of structures containing various TRPC5:EA stoichiometries revealed key structural and molecular determinants of EA-mediated TRPC5 activation – most notably the aromatic interaction network around Phe520 – underscoring the critical function of Met-aromatic motifs in ion channel structure and function. Binding of EA causes conformational changes of nearby amino acid residues, resulting in rearrangement of the pore helices into a pre-open state. Collectively, we provide structural insight into the mode-of-action of the most widely used TRPC4/5 agonist, which will underpin fundamental TRPC4/5 channel research as well as ongoing drug discovery programmes. ### Competing Interest Statement RSB and DJB are scientific co-founders and partners of the pharmaceutical start-up company CalTIC GmbH. RSB, DJB and SAP have received funding from CalTIC GmbH. DJB is an inventor on the following patent applications: (1) PCT/GB2018/050369. TRPC ion channel inhibitors for use in therapy. Filing date: 9th February 2018; (2) 62/529,063. Englerin derivatives for the treatment of cancer. Filing date: 6th July 2017. The other authors declare no competing interest. Biotechnology and Biological Sciences Research Council, https://ror.org/00cwqg982, BB/P020208/1, BB/Z514925/1 British Heart Foundation, https://ror.org/02wdwnk04 Royal Society, WL150028 Wellcome Trust, 108466/Z/15/Z, 221524/Z/20/Z, 218785/Z/19/Z Grant Agency of the Czech Republic, GACR 24-10147S [1]: #ref-1 [2]: #ref-3 [3]: #ref-4 [4]: #ref-5 [5]: #ref-6

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well-structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point-in-time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70231. The Concise Guides provide expert-curated recommendations of 'Gold Standard' selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid-2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

PIEZO1 variants have been associated with generalized lymphatic dysplasia (GLD) through mechanisms involving reduced PIEZO1 expression. Here, we report variants where the mechanism involves reduced channel mechanical sensitivity. Two of the variants encode amino acid changes in the channel's cap structure (Ile2270Thr and Arg2335Gln), one in the ninth transmembrane helical unit (THU) below the cap (Gly1978Asp) and one in the fifth THU distant from the cap (Glu829Val). Patch-clamp studies of the cap and sub-cap variant channels revealed abolished or reduced channel mechanical sensitivity with the possibility to activate the channels and partly rescue mechanical sensitivity by the small molecule Yoda1. The potency of Yoda1 at the variant channels was less than at the wild-type channel, but chemical synthesis of Yoda1 analogs revealed a molecule with improved potency. The data suggest cases of GLD in which there is decreased channel mechanical sensitivity and the potential to reduce dysfunction pharmacologically.

PIEZOs form trimeric calcium-permeable nonselective cationic channels that serve mechanical sensing needs across eukaryotic biology. Forces act on the channels by causing their curved blades to flatten and decompact, leading to an activated state, but it is unclear how this is regulated to enable the channels to adapt to different contexts. To identify potential mechanisms, we performed coarse-grained and all-atom molecular dynamics simulations on human PIEZO1. We observed an interblade handshake interaction mediated by basic amino acid residues in two flexible helices coordinated with regulated anionic lipid phosphatidylinositol 4,5-bisphosphate. The interaction determined the resting configuration of the channel, blade curvature, compactness, and ion pore structure. In experiments, disruption of the handshake by neutralization of helix amino acids or phosphatidylinositol 4,5-bisphosphate depletion increased the channel's sensitivity to membrane tension. Structural and amino acid sequence analysis for multiple PIEZOs predicted helix amino acid arrangements for varied handshaking intensity. We suggest a dynamic interaction in PIEZO channels that regulates force sensitivity.

The discovery of PIEZO1 channels as robust, rapidly activating, electrically transducing mechanical force sensors of endothelial biology led to intense research efforts that have transformed the appreciation and understanding of pivotal relationships between mechanical forces and cardiovascular health. This narrative review of the scientific literature highlights discoveries about the PIEZOs, PIEZO1 and PIEZO2, in vascular biology from the embryo to adult stages including in vascular and valve formations, vascular expansion and arrest, lymphatic and venous integrity, blood pressure regulation, the aortic baroreceptor reflex, microvascular density for muscle and physical exercise capabilities and the regulation of lipid homeostasis, cerebral hyperemia and leukocyte extravasation. Concepts are discussed for how the channels work at the molecular level and integrate with other cell components and how they signal downstream for appropriate tissue responses. A PIEZO-centric hypothesis is debated for the core fluid flow sensing property of cardiovascular biology. PIEZO contributions to vascular and vascular related disease problems are discussed. In summary, this is an exciting area of research that is revolutionizing the understanding of the cardiovascular system and revealing new ways to address unsolved cardiovascular disease.