Endothelial intracellular calcium (Ca2+) signaling is a multi-scale control system that couples external stimuli (shear stress, vasoactive agonists, inflammatory mediators) to nitric oxide (NO) production, endothelium-derived hyperpolarization, barrier integrity, angiogenesis, and regulated exocytosis of prothrombotic mediators. Contemporary "endothelial Ca2+ code" frameworks emphasize that spatially restricted microdomain events, such as TRPV4 "sparklets," IP3R "pulsars/wavelets," and Piezo1-driven mechanochemical transduction, are decoded into functionally specific outputs, while organellar Ca2+ handling from the ER/SR and the mitochondria tunes amplitude, duration, and translation into redox/inflammatory responses. This framework is particularly relevant for toxicology because divalent toxicants can alter not only the magnitude but also the spatial logic of endothelial Ca2+ signaling (Moccia et al. 2023).Heavy metals and metalloids, including lead (Pb), cadmium (Cd), mercury (Hg; particularly methylmercury), and inorganic arsenic (As), are increasingly recognized as cardiovascular risk factors capable of perturbing this endothelial Ca2+ code early in exposure. Mechanistically, these toxicants (i) impersonate Ca2+ or opportunistically bind Ca2+-binding motifs, (ii) enter through or modulate Ca2+-permeable channels (notably TRP and store-operated pathways), (iii) impair pumps/exchangers or provoke ER stress, and (iv) trigger oxidative stress and inflammatory signaling that reciprocally reshapes Ca2+ dynamics and NO bioavailability. The resulting Ca2+/redox feed-forward loops can shift the endothelium toward vasoconstriction, permeability, leukocyte adhesion, dysregulated angiogenesis, and thrombosis. Experimental studies of Pb2+ cardiotoxicity and Ca2+ antagonism, together with broader exposome analyses of Pb and Hg, support the concept that divalent toxicants can act as calcium-mimetic cardiovascular stressors with direct consequences for calcium-dependent signaling (Chavarría et al. 2021; de Mattos et al. 2017; Ferreira et al. 2021a).This review synthesizes endothelial Ca2+ physiology; molecular Ca2+ handling nodes (channels, pumps, exchangers; ER/SR and mitochondria); evidence that Pb, Hg, Cd, and As disrupt Ca2+ homeostasis; downstream dysfunction phenotypes; dose-response and population vulnerability considerations; experimental models and methods; and mitigation strategies and knowledge gaps.
The advent of sodium-glucose co-transporter (SGLT) inhibitors - including selective SGLT2 and dual SGLT1/2 agents - has redefined cardiorenometabolic therapy, markedly reducing cardiovascular events, heart failure hospitalizations, and kidney disease progression in patients with and without diabetes. Despite their robust and well-documented benefits, uptake is sometimes limited in specific patient groups, often reflecting concerns about adverse effects. Traditionally reported risks - including hypoglycemia, euglycemic diabetic ketoacidosis, volume depletion, acute kidney injury, genital and urinary tract infections, bone fractures, and lower limb amputations - exhibit heterogeneous clinical relevance; some are not consistently reproduced or are of uncertain clinical significance, whereas others are rare but clinically meaningful and modulated by patient phenotype, comorbidities, and concomitant therapies. Drawing on large cardiovascular and renal outcome trials, supplemented by real-world evidence, which provide estimates of both absolute and relative risks, this chapter offers an evidence-based framework to anticipate, recognize, and mitigate complications, supporting the safe and effective integration of SGLT inhibitors across diverse clinical populations.
The introduction of the sodium-glucose cotransporter-2 inhibitors (SGLT2i) was a landmark moment in the treatment of diabetes. Their unique insulin independent mechanism of action, results in decreased reabsorption of glucose at the renal tubular level and increased glucosuria, which lowers blood glucose along with modest weight reduction due to caloric loss in the urine. Today, the SGLT2i are approved not only for their glycemic benefits, but also to reduce the risk of heart failure (HF) hospitalization and progression to chronic kidney disease (CKD) in patients with type 2 diabetes (T2DM) and CKD/HF. Notably, the SGLT2i are also approved for cardiorenal benefits in those without diabetes. However, SGLT2i are not approved for use in those with type 1 diabetes (T1DM) due to the increased risk for diabetic ketoacidosis (DKA) and euglycemic ketoacidosis. This review provides an overview of the various metabolic effects seen with the use of SGLT2i and dual SGLT1/2 inhibitors in patients with T1DM, including beneficial effects on glycemia despite a paradoxical increase in endogenous glucose production (EGP), changes in insulin sensitivity, hyperglucagonemia and changes in substrate oxidation. We also discuss mechanisms leading to increased ketogenesis and a higher risk of DKA in those with T1DM and potential measures to mitigate this risk, so that patients with T1DM can safely avail the robust glycemic and cardiorenal benefits of these agents.
Carboranes are boron-rich polyhedral clusters with unique physicochemical properties, including high hydrophobicity, three-dimensional structure, and the ability to act as bioisosteres of aromatic groups. These features make them attractive building blocks in medicinal chemistry. This chapter summarizes recent advances in the design of carborane-containing derivatives of biologically active scaffolds, including 1,8-naphthalimides, acridines, penicillin G, and isoniazid.The incorporation of carborane clusters significantly influenced the biological activity of parent compounds by modulating DNA interactions, anticancer mechanisms, antibacterial activity, lipophilicity, and membrane permeability. In anticancer conjugates, carborane modification affected DNA binding, reactive oxygen species generation, apoptosis induction, and cellular localization. In antibacterial agents, carborane incorporation improved the activity of selected penicillin G and isoniazid derivatives, including activity against resistant bacterial strains.These examples demonstrate that carboranes are versatile pharmacophores capable of enhancing the biological properties of established drug scaffolds and represent promising tools for the development of novel anticancer and antimicrobial agents.
Boron has emerged as a versatile element in medicinal chemistry because its empty p-orbital enables reversible covalent interactions with biologically important nucleophiles while supporting diverse, tunable molecular architectures. Following approval of bortezomib in 2003, boron-containing therapeutics have expanded beyond proteasome inhibition to infectious disease, inflammation, thrombosis, metabolic and cardiovascular disease, cancer immunotherapy, and boron neutron capture therapy (BNCT). This chapter critically surveys boron-containing candidates that have entered clinical trials, organizing them by scaffold class: boronic acids, borinic acids, benzoxaboroles, cyclic boron heterocycles, and boron clusters. The agents reviewed include borofalan, delanzomib, flovagatran, dutogliptin, talabostat, numidargistat, OATD-02, AN0128, epetraborole, ganfeborole, acoziborole, taniborbactam, xeruborbactam, and sodium borocaptate, as well as the five FDA-approved boroncontaining drugs (bortezomib, ixazomib, crisaborole, tavaborole, vaborbactam). Their mechanisms, pharmacokinetics, clinical efficacy, safety, regulatory status, and development trajectories are compared. Collectively, the clinical evidence illustrates how boron chemistry enables selective target engagement through reversible covalent inhibition, tRNA trapping, β-lactamase blockade, arginase modulation, and isotope-mediated cellular destruction. Particularly notable advances include borofalan-based BNCT for head and neck cancer, single-dose acoziborole for gambiense human African trypanosomiasis, ganfeborole-containing regimens for tuberculosis, and broad-spectrum cyclic boronate β-lactamase inhibitors designed to restore antibiotic activity against multidrug-resistant Gram-negative pathogens. Across programs, most candidates were generally well tolerated, whereas discontinuations frequently reflected inadequate comparative efficacy, commercial competition, funding limitations, or manufacturing requirements rather than intrinsic boron toxicity. The histories of dutogliptin and talabostat further demonstrate that mechanistically distinctive boron compounds may be successfully repositioned after setbacks in their original indications. Together, these findings show that boron's structural versatility, low inherent toxicity, and capacity for precise, often reversible target binding continue to support productive clinical translation. The review also highlights how clinical success depends on matching pharmacology with unmet need, feasible administration, competitive differentiation, and durable development partnerships. Ongoing advances in scaffold design, delivery, combination therapy, and indication selection are expected to broaden the therapeutic impact of boron-containing medicines.
BODIPY and aza-BODIPY fluorophores have attracted considerable attention in theragnostic research because of their excellent photophysical properties, high photostability, structural versatility, and ease of chemical functionalization. These characteristics have enabled their application in fluorescence imaging, molecular sensing, photodynamic therapy (PDT), photothermal therapy (PTT), and multifunctional nanoplatforms for diagnosis and treatment. This chapter reviews recent advances in the molecular engineering of BODIPY- and aza-BODIPY-based systems, emphasizing the structural strategies used to modulate their optical properties and therapeutic performance. Particular attention is devoted to the development of activatable probes, photosensitizers, responsive molecular sensors, and nanostructured theragnostic platforms. The discussion highlights how rational molecular design has expanded the biomedical potential of these fluorophores and identifies current challenges and future opportunities for the development of next-generation fluorescent theragnostic agents.
The first quarter of the twenty-first century has seen a rapid expansion of research into the medical applications of boron cluster-based compounds. Key areas of this research include the use of polyhedral boron hydrides (carboranes, boranes, and metallacarboranes) as pharmacophore groups in the synthesis of compounds with various types of biological activity, the synthesis of boron-rich compounds for boron neutron capture cancer therapy, and the use of boron clusters as carriers of radiohalogen label in radionuclide diagnostics and therapy. This is an attempt to demonstrate the diversity of research being conducted and to briefly touch upon the most interesting results obtained in this area.
Icosahedral boron clusters have gained increasing attention as biomedical platforms for integrated imaging and therapy. Their outstanding chemical and metabolic stability, high boron density, and structural adaptability enable the design of multifunctional agents that combine diagnosis and treatment within a single molecular or nanoscale construct. This chapter focuses on the biomedical exploitation of boron cluster-based systems for cellular bioimaging and in vivo theranostics, with particular emphasis on boron neutron capture therapy (BNCT). At the in vitro level, boron clusters have been incorporated into fluorescent probes and photoactive conjugates to investigate structure-property-activity relationships, cellular uptake, organelle targeting, and photodamage and illustrate how subcellular localization controls combined BNCT and photodynamic efficacy. In vivo, Gd-carborane systems exemplify MRI-guided BNCT and GdNCT, evolving from LDL-based nanoplatforms to CAIX-targeted small molecules that couple image-based dosimetry with dual neutron capture at the tumour site. Complementary PET/SPECT-radiolabelled boron clusters and nanocarriers enable quantitative tracking of boron biodistribution, patient selection, and irradiation timing. Furthermore, targeted and nanostructured formulations improve tumour selectivity and therapeutic efficacy while reducing off-target toxicity. This chapter highlights how icosahedral boron clusters have evolved into clinically relevant theranostic platforms that integrate imaging, dosimetry, and therapy, supporting the development of more precise and personalized strategies in cancer diagnosis and treatment.
Glioblastoma remains among the most aggressive and treatment-refractory brain tumors, prompting the exploration of alternative therapeutic strategies. Boron clusters including carboranes, metallacarboranes, and dodecaborate-based systems have gained attention as chemically versatile motifs that combine high boron density with unique biological functionality. This chapter reviews recent developments, together with selected seminal studies, in the use of boron cluster-based approaches for potential glioblastoma treatment. Strategies spanning nanostructured delivery platforms and molecularly targeted small molecules are discussed, with emphasis on structure-activity relationships, biological mechanisms, and their integration with boron neutron capture therapy.
Most TAAR-related drug discovery research which has advanced to clinical trials has focused on neuropsychiatric disease. Unfortunately, most studies are either conducted on males only or male and female data are not presented separately to inform on sex specificity of findings. As sex bias is highly prevalent in neuropsychiatric disease, this relative lack of considering sex as a potential confounding factor in these studies hampers complete elucidation of mechanisms at play. Therefore, in this chapter, we focus on the three TAARs for which most research data have been generated (TAAR1, TAAR5 and TAAR8) and summarise sex differences that have been reported in terms of TAAR expression and/or function, with consideration of species differences. In addition, given the sparsity of this information, we expanded our literature search to also include a discussion of role players at different levels of the trace amine signalling pathways - e.g. TAAR ligands. The role of oestrogen as potential TAAR modulator is also discussed. Integrating this information, we provide a critical discussion on whether significant sex differences are likely to exist in TAAR signalling. Finally, we make recommendations on research priorities going forward to ensure that TAAR-focused therapeutics development research is equally beneficial to both males and females.
Substantial evidence indicates that stress serves as a major risk factor for various psychiatric disorders, including major depressive disorder (MDD), anxiety disorders, post-traumatic stress disorder (PTSD), and bipolar disorder. Although multiple therapeutic options exist for these conditions, current treatments often fall short of meeting clinical needs. Since the identification of trace amine-associated receptor 1 (TAAR1), studies across diverse animal models have revealed its involvement in modulating stress responses and its potential role in stress-related psychopathologies. Several selective TAAR1 agonists have shown promising efficacy in alleviating certain stress-induced adverse effects. While the underlying mechanisms remain incompletely understood, emerging evidence suggests they may involve TAAR1 expression in key brain regions regulating stress, as well as its modulatory effects on neurotransmitter systems - such as dopamine, serotonin, and glutamate. This chapter summarizes current research on TAAR1, with a focus on the role of TAAR1 ligands in stress-related disorders. Additionally, we briefly discuss TAAR1-related signaling pathways in stress regulation and the pharmacology of TAAR1 agonists.
The Na+-coupled glucose transporter SGLT2 is expressed in the early proximal tubule of the kidney, where it reabsorbs most of the filtered glucose. Drugs that inhibit SGLT2 (SGLT2i) can protect the kidneys in patients with and without type 2 diabetes mellitus. In a nutshell, SGLT2i shift the reabsorption of large amounts of glucose from the early proximal tubule to downstream tubular segments that take up glucose via SGLT1. Non-reabsorbed glucose is lost into the urine associated with an osmotic diuresis. Why should this protect the kidney? This review first outlines the physiology of kidney glucose transport. Then it outlines how primary effects of SGLT2i on the early proximal tubule can explain clinical phenotypes that, according to mediation analyses, are predictors of kidney (and heart) protection by SGLT2i, including an increase in hematocrit and lowering of plasma volume, serum urate levels, and albuminuria. Tubule-glomerular communication forms the physiological basis for SGLT2i to acutely lower glomerular filtration rate (GFR) and glomerular capillary pressure. This lowers albuminuria and kidney cortex oxygen demand, which both preserve tubular integrity and GFR in the long run. In the early proximal tubule, SGLT2 is functionally co-regulated with other apical sodium and metabolite transporters. This explains why SGLT2i initially excrete more sodium than expected and are uricosuric, lowering plasma volume and serum urate levels. SGLT2i lower early proximal tubule glucotoxicity and by shifting transport downstream better distribute tubular transport burden and energy needs. Moreover, the transport shift tricks the kidney by simulating "systemic hypoxia" at the oxygen sensors in outer medullary interstitial cells. The resulting release of erythropoietin, together with the osmotic diuresis, enhances hematocrit and thereby oxygen delivery to kidneys and other organs. This is complemented by an SGLT2i-induced insulin-sparing and fasting-like metabolic and anti-inflammatory phenotype and by off-target effects including less microbiotic formation of uremic toxins.
Trace amine-associated receptors (TAARs) were originally identified as G protein-coupled receptors involved in monoaminergic signaling within the central nervous system. However, accumulating evidence indicates that TAARs, particularly TAAR1 and TAAR2, are also expressed in the immune system, including circulating leukocytes, lymphocytes, macrophages, and microglia. This chapter reviews current evidence regarding TAAR expression, functional pharmacology, and potential translational relevance within the immune system.Expression studies support a predominant TAAR1/TAAR2 pattern across both innate and adaptive immune-cell populations. Functional studies indicate that TAAR signaling can modulate inflammatory responses through chemotaxis, cytokine production, and immunoglobulin secretion. However, these effects are highly context-dependent, preventing a simple classification of TAAR signaling as either pro-inflammatory or anti-inflammatory.The chapter also discusses the emerging role of TAAR signaling in the pathophysiology of diseases, including inflammatory bowel disease, methamphetamine-associated immune dysfunction during HIV infection, multiple sclerosis, Parkinson's disease, fibromyalgia, and hematological malignancies.Despite growing interest in TAAR immunopharmacology, the current evidence remains largely preclinical and methodologically heterogeneous. Major limitations include incomplete protein-level validation, reliance on immortalized cell lines or mixed-cell populations, species-specific pharmacology of available ligands, and limited understanding of physiological trace amine signaling under basal conditions. Further integrative studies will be required to clarify TAAR pathophysiological significance and determine whether TAAR-targeted strategies may have translational relevance in immune-mediated disorders.
Gestational diabetes mellitus (GDM) is increasingly diagnosed in women strongly driven by the increase in overweight and obesity in women of childbearing age, yet the literature still addresses this condition more often through the lens of diagnostic glucose thresholds and subsequent nutritional management of glycaemia than through broader concepts of glycaemic dynamics, vascular dysfunction and phenotypic heterogeneity. Both GDM and maternal obesity are associated with altered glycaemia, increased glycaemic variability and endothelial dysfunction within the foetoplacental circulation, with potential consequences for nutrient transfer, foetal growth and later cardiometabolic risk. When these conditions coexist, i.e. gestational diabesity, metabolic and vascular disturbances may be amplified. This review critically examines current evidence on dietary patterns, macronutrients, micronutrients and selected bioactive compounds with hypoglycaemic properties in GDM. Attention is given to CGM-derived indices of glycaemic dynamics and to nutritional mechanisms plausibly linked to endothelial function, including oxidative stress, nitric oxide bioavailability, inflammation and insulin sensitivity. Overall, the evidence suggests promise for higher-quality carbohydrates, dietary fibre, increased protein intake, myo-inositol, vitamin D, selected trace elements, omega-3 fatty acids and probiotics; however, the field is constrained by short interventions, heterogeneous populations, limited use of CGM and a heavy reliance on surrogate metabolic endpoints rather than direct vascular assessment. A more mechanistic and phenotype-aware research strategy is therefore needed before specific nutritional approaches can be considered established tools for improving both glycaemic dynamics and vascular function in GDM and gestational diabesity.
Based on a significant amount of evidence from in vitro, animal, and human experiments, the basic aspect of the mechanism of action of nutritional, pharmacological, and toxicologic inorganic boron is the formation of boron esters with biomolecules that have vicinal cis-diols. The formation of boron esters results in the modulation of the bioactivity of biomolecules, especially those with the ribose moiety, that regulate gene expression, inflammation, oxidation/reduction, membrane function, hormone activity, and signaling. The nutritional and pharmacological modulation has been found to have benefits under conditions with impaired bone formation and maintenance, cognitive function, psychomotor skills, cancer risk, cardiovascular disease, diabetes, immune function, inflammatory symptoms in osteoarthritis and dental disease, embryo development, and aging. Because there is evidence that impairments in these functions occur in animals and humans fed boron-deprived diets, the identification of a mechanism of action supports the concept that boron is a nutrient needed for optimal health and well-being.
Boron neutron capture therapy (BNCT) is an emerging modality for cancer treatment, where the development of advanced boron-containing drugs is crucial. Recent years have seen the application of boron-containing drugs exhibiting high boron content, excellent tumor-targeting ability, low toxicity, and good biocompatibility in BNCT for diverse cancers, including skin, breast, and brain tumors. Nevertheless, challenges persist in boron-containing drug development, notably the inability to monitor drug distribution in vivo, which impedes the precise application of neutron irradiation. Fluorescence imaging, recognized for its capacity to detect biomolecules in real time and multiple dimensions, has emerged as a promising solution. Consequently, researchers have proposed designing "luminescent boron-containing drugs" to enable precise spatial and concentration mapping via fluorescence imaging. This chapter provides a concise overview of BNCT, boron-containing drugs, and fluorescence imaging, followed by a detailed discussion on molecular design strategies and applications of photo-functional boron-containing drugs for integrated imaging diagnosis and BNCT treatment. Within this framework, advanced boron-containing drugs incorporating fluorescence imaging capabilities-such as near-infrared, two-photon absorption, and fluorescence lifetime imaging-are being developed. With ongoing research efforts, fluorescence-imaging boron-containing drugs hold significant potential for future clinical BNCT, ultimately benefiting patients.
Insulin and glucagon secreted by beta- and alpha-cells of the islets of Langerhans, respectively, regulate tissue glucose uptake, metabolism, and glycolysis. Islets represent around 2% of pancreatic mass but receive around 20% of the arterial blood flow; arteriolar blood entering the islet giving rise to a dense, fenestrated capillary bed enabling rapid glucose sensing and prompt hormone excretion. Local regulation of blood flow within each islet is achieved by contractile pericytes lining the capillaries. Endothelial cells and pericytes contribute to the lineage commitment and maturation of islet endocrine cells in utero, which can be disrupted by maternal under- or over-nutrition. Vascular cells generate the basement membranes juxtaposing endocrine cells and ensure optimal endocrine function. In type 2 diabetes, the intra-islet capillary density is increased but capillary walls are thickened with loss of fenestration and dysregulated hormone release. De-differentiation of pericytes to myofibroblasts causes islet fibrosis. In type 1 diabetes, this pathology is exacerbated by inflammatory cell-derived cytokine action on vascular cells. Pancreatic cancer-associated diabetes (type 3c), as seen with ductal adenocarcinoma, involves fibrotic thickening of the peri-islet basement membrane caused by tumor-derived growth factors. Conversely, insulin secretion may contribute to cancer growth. Therapeutic options to prevent or delay diabetes include maintaining islet vascular function through limiting cellular oxidative stress and inflammation.
Endothelial cells translate hemodynamic forces into biochemical signals that regulate vascular homeostasis through a process called mechanotransduction. Over the past decades, the study of this physiological process has received significant attention, leading to the identification of molecular structures that detect changes in shear stress. However, the functional capacity of these mechanosensors is compromised under conditions such as obesity, diabetes, and aging, resulting in impaired mechanotransduction. Such impaired mechanotransduction leads to endothelial dysfunction, a key early component of cardiovascular disease. This highlights the importance of studying the molecular and cellular mechanisms underlying endothelial mechanotransduction and its dysfunction. In this chapter, putative molecular components of endothelial mechanotransduction, their signaling pathways, and alterations under both physiological and pathological conditions will be discussed. Accurate identification of these components and a deep understanding of the mechanotransduction mechanisms in which they participate are needed to develop novel therapeutics for cardiovascular disease.
The traditional view of autism spectrum disorder (ASD) has largely focused on neuronal mechanisms as the primary drivers of atypical neurodevelopment. However, increasing evidence suggests that vascular and neurovascular processes also contribute to the developmental trajectories associated with the condition. In particular, endothelial cells have emerged as active regulators of brain development through their roles in angiogenesis, blood-brain barrier (BBB) formation, neurovascular signaling, and interactions with the immune system. This chapter examines the growing body of evidence supporting a neurovascular perspective of ASD, in which endothelial dysfunction is considered a biologically meaningful component of pathophysiology rather than a secondary consequence of neural alterations. Evidence from both human studies and experimental models indicates that disturbances in vascular development, BBB integrity, VEGF signaling, endothelial metabolism, and neuroimmune communication can influence brain maturation and behavior. Particular attention is given to prenatal and perinatal factors, including maternal inflammation, placental dysfunction, and environmental exposures that affect endothelial development during critical periods of neurodevelopment. The chapter also explores the contribution of oxidative and nitrosative stress, endothelial adhesion molecules, and the neurovascular unit as mechanisms linking vascular and neural dysfunction. By integrating findings across molecular, cellular, developmental, and systems-level studies, this work advances a framework in which vascular and neural processes are tightly interconnected throughout brain development. This perspective not only provides new insight into the biological heterogeneity of ASD but also highlights the endothelium and the neurovascular unit as promising targets for biomarker discovery and future therapeutic intervention.
Atherosclerosis, the leading cause of cardiovascular death worldwide, is initiated by endothelial cells (ECs) dysfunction and sustained by maladaptive vascular remodeling. Far from being a uniform barrier, the endothelium is highly heterogeneous and phenotypically plastic. A central manifestation of this plasticity is endothelial-to-mesenchymal transition (EndMT), a dynamic continuum in which ECs progressively lose their endothelial identity and acquire mesenchymal, pro-fibrotic traits that contribute to every stage of atherosclerotic lesion development. This chapter reviews how atherogenic cues, including disturbed blood flow, oxidative stress, inflammation, and extracellular matrix stiffening, trigger EndMT, and how convergent signaling networks, notably TGF-β, together with Wnt/β-catenin, Notch, NF-κB/STAT3, and epigenetic regulators such as HDAC9, drive this process. These pathways are counterbalanced by protective mechanisms, including FGF and KLF2/KLF4 signaling, which help maintain endothelial homeostasis. We summarize evidence from in situ co-staining, genetic lineage tracing, epigenetic fate mapping, and single-cell multi-omics approaches, which collectively reveal distinct disease-associated EC subpopulations. We also review the in vitro, organ-on-a-chip, and murine models used to dissect EC plasticity. Finally, we discuss therapeutic and precision medicine strategies aimed at selectively reprogramming pathogenic endothelial states to promote plaque stabilization while preserving vascular integrity.
