Search Results (379)

Pulsatile blood flow is a fundamental characteristic of cardiovascular physiology that regulates endothelial function, vascular homeostasis, microcirculatory integrity, and organ adaptation through complex mechanobiological pathways. The widespread use of continuous-flow left ventricular assist devices (CF-LVADs) has created a unique clinical model of chronic pulsatility deprivation, whereas heart transplantation restores physiological pulsatile hemodynamics. This review examines the molecular, cellular, and systemic consequences of these contrasting circulatory states. Evidence from experimental and clinical studies indicates that reduced pulsatility during CF-LVAD support is associated with impaired endothelial mechanotransduction, glycocalyx disruption, oxidative stress, inflammatory activation, angiogenic dysregulation, acquired von Willebrand syndrome, and microvascular remodeling. These alterations contribute to bleeding, thrombosis, neurological events, and progressive end-organ dysfunction. In contrast, restoration of pulsatile flow following heart transplantation promotes recovery of endothelial signaling, nitric oxide bioavailability, vascular responsiveness, and tissue perfusion, although persistent immune-mediated injury may limit complete vascular normalization. Emerging concepts involving Piezo1 signaling, YAP/TAZ mechanotransduction, extracellular vesicles, immunometabolism, and multi-omics profiling further support the role of pulsatility as a biological regulator rather than a simple hemodynamic consequence of cardiac contraction. Understanding pulsatility-dependent cardiovascular remodeling may facilitate the development of next-generation circulatory support technologies and novel therapeutic strategies to preserve vascular health. Full article

Caused by the SARS-CoV-2 virus, the COVID-19 pandemic is still considered a complex challenge, with manifestations not only of respiratory issues, but also conditions related to chronic cerebrovascular damage. Endothelial biomarkers, neuropathological and neuroimaging findings indicate endothelial dysfunction, microthrombosis, and disruption of the blood–brain barrier (BBB) are central mechanisms for acute and chronic ischemic and hemorrhagic cerebral events. Understanding these mechanisms is vital to reducing their impact on population health, whether through treatment or prevention of adverse outcomes. The objective of this study is to perform a review of the scientific literature on the post-infection effects of SARS-CoV-2 affecting the cerebral endothelium and the BBB, correlating them with potential clinical outcomes. Material and Methods: Analysis of studies extracted from the PubMed database using the following terms: Long-COVID “AND” SARS-CoV-2 “AND” blood–brain barrier. Inclusion criteria: keywords, publications related to the topic, and primary studies published after peer review. Exclusion criteria: preprint studies, publication outside of the timeframe 2020–2025, study design not compatible with this research, and full text not available. Results: An initial 121 studies were identified, of which 105 were excluded due to not meeting all inclusion criteria and 6 studies were inaccessible due to not being in the English language and full-text access limitations. Fifteen articles were included in the analysis, for topics as expression of viral receptors in the endothelium, markers of their activation, cerebral microvascular injury and coagulopathies. To clarify the pathogenic cascade, the evidence was stratified by biological model where in vitro evidence demonstrates that the Spike protein induces direct endothelial toxicity and platelet aggregation, establishing the primary molecular insult. Animal models confirm the translation of this insult into structural degradation of the BBB and pericyte loss. Clinically, infection-phase findings, characterized by multifocal microthrombosis and permeability spikes, act as the determining event that predisposes to the persistent neuroinflammatory environment. Biomarkers of BBB disruption and neuronal damage were consistently reported, with persistence of BBB dysfunction modifying risk stratification and rehabilitation efforts. Reported cases of Long-COVID demonstrated normalization of BBB markers without correlation with long-term symptoms, suggesting that other mechanisms are involved in Long-COVID. Conclusion: Cerebral endotheliopathies and BBB dysfunction in patients with COVID-19 continue to impact the health of the population. The scientific literature indicates that SARS-CoV-2 induces cerebral endothelial injury, BBB disruption, and an increased risk of vascular events related to endotheliopathy, inflammation, and hypercoagulability. Understanding the impact of COVID-19 pathology on the population and developing prospective studies is essential to quantify the prevalence and mechanisms of brain injury. The identification of molecular targets and infection pathways are promising toward defining both preventive and therapeutic strategies to improve outcomes in the Long-COVID population. Full article

Diabetic kidney disease (DKD) remains one of the most severe microvascular complications of type 2 diabetes mellitus (T2DM) and a leading cause of chronic kidney disease (CKD) worldwide. Nevertheless, despite considerable progress in elucidating its molecular background, early diagnosis and accurate stratification of disease progression remain challenging when relying on conventional clinical biomarkers such as albuminuria and estimated glomerular filtration rate (eGFR). Growing evidence indicates that DKD is driven by interconnected pathogenic mechanisms, including chronic hyperglycemia, activation of the protein kinase C (PKC) signaling pathway, renin–angiotensin–aldosterone system (RAAS) dysregulation, oxidative stress, inflammatory cascades, and immune system activation involving Toll-like receptors (TLR) and the NLRP3 inflammasome. These processes collectively contribute to endothelial dysfunction, podocyte injury, extracellular matrix accumulation, and progressive renal fibrosis. Exosomes and their molecular cargo, particularly miRNAs, have emerged as promising regulators and non-invasive biomarkers reflecting ongoing renal injury. Urinary exosomal microRNAs (uEV-miRNAs) are of interest due to their stability in biological fluids and their direct origin from nephron segments, enabling real-time reflection of renal pathophysiology. Accumulating studies suggest that differentially expressed microRNAs (miRNAs), including miR-21-5p, miR-30a-5p, miR-192-5p, and miR-142-3p, are closely associated with key pathways in DN. However, their clinical translation remains limited by methodological heterogeneity, the lack of standardized isolation protocols, and insufficient validation in large longitudinal cohorts. This review navigates the current landscape of knowledge on the molecular mechanisms underlying DKD and examines the emerging role of uEV-miRNAs as diagnostic biomarkers. Altogether, uEV-miRNAs offer a promising avenue for improving early detection, risk stratification, and disease monitoring in DKD. Full article

Background/Objectives: Type 2 diabetes is increasingly recognized as a systemic disorder driven not only by chronic hyperglycemia and insulin resistance, but also by dysregulated interorgan communication. Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as biologically active carriers of proteins, lipids, and microRNAs capable of modulating gene expression in recipient cells. This narrative review integrates clinical, experimental, and translational evidence on EV-associated microRNAs as candidate biomarkers and potential mediators of diabetic complications, with emphasis on diabetic neuropathy, diabetic kidney disease, diabetic retinopathy, and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This review was aligned with the SANRA framework and focused on biological plausibility, evidence from tissue and biofluids, biomarker potential, therapeutic implications, and barriers to clinical translation. Studies were additionally interpreted according to biological matrix, EV-carrier specificity, analytical platform, study design, and level of functional validation. Results: Across complications, EV-associated microRNAs appear to participate in shared pathogenic processes, including oxidative stress, inflammation, endothelial dysfunction, fibrosis, angiogenesis, neurodegeneration, and metabolic memory. In diabetic neuropathy, microRNAs such as miR-146a, miR-155, miR-21-5p, and miR-148a-3p have been linked to neuroinflammation, Schwann-cell dysfunction, axonal injury, and neuropathic pain. In diabetic kidney disease, miR-21, miR-29, miR-30, and miR-126 are implicated in podocyte injury, tubulointerstitial fibrosis, albuminuria, and microvascular dysfunction. In diabetic retinopathy, microRNAs including miR-146a, miR-155, miR-21, miR-126, and miR-200b contribute to neurovascular injury, inflammation, barrier disruption, and angiogenesis. In MASLD associated with diabetes, hepatocyte-derived EVs carrying microRNAs such as miR-1 and miR-126a-3p may link hepatic lipotoxicity to endothelial inflammatory and β-cell dysfunction. Conclusions: Although EV-associated microRNAs offer promising opportunities for biomarker discovery, risk stratification, and targeted therapies, clinical translation remains limited by heterogeneity in EV isolation, microRNA quantification, biological matrices, and outcome definitions. Distinguishing EV-associated miRNAs from total circulating extracellular miRNAs remains essential for biological interpretation. Standardized, longitudinal, and externally validated studies are required before these signals can be implemented as actionable tools in precision diabetes care. Full article

Preeclampsia is a serious pregnancy complication characterised by maternal vascular dysfunction, placental dysfunction, and organ injury, with no effective treatment currently available. Kampo, a system of Japanese traditional medicine comprising standardised herbal formulations, could target pathophysiological pathways driving preeclampsia. We evaluated the effects of select Kampo formulations on markers of preeclampsia using primary human trophoblasts, placental explants, human umbilical vein endothelial cells (HUVECs), and uterine microvascular endothelial cells (UtMVECs). Twelve formulations were initially screened in HUVECs, and six formulations advanced for further study. TNFα was used to induce endothelial dysfunction, and angiogenic, antioxidant, inflammatory, and vascular dysfunction markers were assessed. Overall, Kampo formulations had minimal effect on sFlt-1 expression and only modest effects on sFlt-1 secretion by primary human trophoblast. In contrast, several formulations consistently increased placental growth factor (PlGF) expression and secretion, upregulated HMOX1 in trophoblasts, and enhanced PlGF secretion from placental explants. In endothelial cells, Kampo treatment partially reversed TNFα-induced dysfunction, demonstrated by reduced VCAM1 expression, and additional endothelial cell type-dependent effects on ET-1 and inflammatory pathways. These findings indicate that selected Kampo formulations modulate key pathways involved in the pathophysiology underpinning preeclampsia and warrant further investigation as potential therapeutic candidates. Full article

Ischemia with non-obstructive coronary arteries (INOCA) and coronary microvascular dysfunction (CMD) are increasingly recognized causes of angina, reduced quality of life, and elevated cardiovascular risk, yet mechanistic heterogeneity complicates diagnosis and treatment. This narrative review synthesizes evidence from clinical guidelines, consensus documents, landmark trials, cohorts, mechanistic studies, and high-quality reviews identified through structured, non-exhaustive searches of PubMed/MEDLINE, Google Scholar, and major cardiovascular society documents. Current evidence indicates that endothelial mitochondria function primarily as signaling organelles, regulating reactive oxygen species, nitric oxide bioavailability, endothelium-dependent hyperpolarization, calcium signaling, inflammatory activation, mitophagy, and endothelial survival. Cardiometabolic risk factors, aging, chronic kidney disease, and postmenopausal hormonal changes may converge on mitochondrial quality-control and redox pathways, contributing to CMD susceptibility and sex-specific vulnerability. However, direct human evidence linking endothelial mitochondrial dysfunction causally to CMD defined by invasive coronary function testing remains limited. Coronary physiological testing and acetylcholine provocation are validated tools for CMD endotyping, whereas mitochondrial biomarkers remain investigational. Endotype-guided diagnosis and management remain central, while mitochondria-targeted strategies require prospective CMD-specific validation. Full article

Diabetic retinopathy (DR) is a leading cause of vision loss among working-age adults and is characterized by progressive retinal microvascular dysfunction driven by hyperglycemia-induced inflammation and oxidative stress. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase involved in multiple cellular processes, has been implicated in vascular pathology; however, its specific role in retinal endothelial cells remains unclear. In this study, we investigated whether endothelial-specific deletion of HDAC6 protects against diabetic retinal injury. Endothelial HDAC6 knockout mice were generated using VE-cadherin–Cre recombination and subjected to streptozotocin-induced diabetes. Retinal vascular integrity, inflammatory and oxidative stress responses, endothelial senescence, and visual function were assessed during the course of hyperglycemia. Diabetic control mice developed characteristic features of DR, including vascular dysfunction, heightened inflammatory and oxidative stress responses, increased endothelial senescence, and impaired visual function. In contrast, endothelial-specific HDAC6 deletion markedly attenuated these pathological changes, preserving retinal vascular integrity and visual performance while reducing oxidative stress and inflammation. These findings identify endothelial HDAC6 as a key contributor to diabetes-induced retinal vascular injury and suggest that targeting endothelial HDAC6 may represent a promising therapeutic strategy for preventing microvascular damage and vision loss in DR. Full article

Heparin-binding protein (HBP) is an activation-dependent neutrophil granule protein involved in innate immune activation, endothelial barrier disruption, and inflammatory tissue injury. Although HBP has been extensively investigated in infectious diseases, particularly sepsis, its potential relevance to transplantation has only recently attracted attention. Several post-transplant complications, including infection, ischemia–reperfusion injury (IRI), microvascular dysfunction, and allograft rejection, share common pathological features such as neutrophil activation, endothelial injury, and excessive inflammatory amplification, suggesting a possible mechanistic role for HBP. This review summarizes the current understanding of HBP biology and evaluates its potential contribution to transplant-associated complications. We also discuss the feasibility of using HBP as an early biomarker for infection surveillance, inflammatory risk stratification, and graft injury monitoring. Furthermore, emerging therapeutic approaches targeting HBP or HBP-mediated vascular inflammation, including neutralizing antibodies, heparin derivatives, and albumin, are critically assessed. While experimental studies have provided preliminary evidence supporting HBP-targeted intervention, clinical validation in transplant populations remains insufficient. Future studies should define the temporal dynamics, cellular sources, and context-specific effects of HBP after transplantation. Collectively, available evidence indicates that HBP may serve as a potential biomarker and therapeutic target, but its clinical application requires further validation through mechanistic and prospective studies. Full article

Background/Objectives: Microvascular dysfunction is a common early manifestation of connective tissue diseases (CTDs), yet practical non-invasive tools remain limited beyond nailfold capillaroscopy. Flow-mediated skin fluorescence (FMSF), based on changes in nicotinamide adenine dinucleotide (NADH) fluorescence during brachial artery occlusion and reperfusion, is thought to reflect microvascular and mitochondrial function. We investigated whether FMSF differentiates CTD subgroups and how its parameters relate to capillaroscopic findings. Methods: In this exploratory cross-sectional study, we examined 99 adults: 19 with lupus erythematosus (LE), 25 with primary Raynaud phenomenon (PR), 29 within the systemic sclerosis (SSc) spectrum, and 26 healthy controls. FMSF parameters were compared across subgroups and capillaroscopic patterns (normal, nonspecific, scleroderma-like) using false discovery rate (FDR) correction and age adjustment. Results: Ten of 19 FMSF parameters differed among subgroups (all FDR-corrected p ≤ 0.03); after age adjustment, four remained significant (PSD1, endothelial and myogenic oscillations, and hypoxia sensitivity [HS]; all p ≤ 0.023), a gradient driven largely by the SSc spectrum. These differences attenuated to non-significance after excluding vasoactive-treated patients (HS p = 0.29) and when restricted to an overlapping age range (p = 0.06–0.18). Across capillaroscopic patterns, the hyperemic response index and HR max declined toward scleroderma-like patterns (both p = 0.007), but no parameter remained associated with pattern after adjustment for CTD diagnosis. Conclusions: Our pilot study provides valuable, though exploratory findings: the FMSF signal was largely SSc-driven and sensitive to treatment and age, rather than a robust, disease-independent discriminator. Confirmation in larger, longitudinal cohorts is required. Full article

Although salivary glands are highly vascularized, the microvascular endothelial barrier has only recently emerged as a pivotal determinant of glandular homeostasis and disease. This review synthesizes current understanding of the salivary gland endothelial barrier, with particular emphasis on the regulation of tight junctions (TJs). Structurally, the barrier comprises endothelial cells interconnected by TJs and adherens junctions, supported by a basement membrane and pericytes. Among TJ components, claudin-5 serves as a key endothelial-specific regulator of paracellular permeability, and is dynamically modulated by biochemical and mechanical stimuli during saliva secretion. Cholinergic, adrenergic, and neuropeptide signaling pathways coordinate to fine-tune endothelial permeability to meet the fluctuating secretory demands. Conversely, under pathological conditions, such as Sjögren’s syndrome, radiation-induced injury, diabetes mellitus, fibrotic diseases, and salivary gland tumors, the integrity of the endothelial TJ complex is impaired. These pathologies are characterized by aberrant TJ expression, mislocalization, and signaling-mediated junctional disassembly, which trigger vascular leakage and immune cell infiltration—two key processes that act as primary drivers of glandular dysfunction. Collectively, these findings enrich our understanding of the microvascular mechanisms that link endothelial barrier function to salivation, and highlight that the restoration of junctional integrity is a promising therapeutic strategy for salivary gland diseases. Full article

The vascular endothelial glycocalyx (EGX) is a gel-like, negatively charged mesh of membrane-bound proteoglycans, glycosaminoglycans, glycoproteins and adsorbed plasma proteins that covers the luminal surface of the endothelium and orchestrates vascular homeostasis through regulation of permeability, leukocyte trafficking, mechanotransduction and anti-thrombotic signalling. Progressive thinning, heterogeneous remodelling and accelerated shedding of the EGX are now recognised as hallmarks of vascular ageing and early drivers of age-related cardiovascular disease. Here, we synthesise current evidence linking EGX integrity to biological ageing, with emphasis on age-dependent remodelling of heparan-sulfate proteoglycans, endothelial progenitor-cell dysfunction, and the heightened susceptibility of the aged EGX to oxidative, inflammatory and infectious insults. We discuss signalling pathways driving EGX shedding—including the IQGAP1/PAR1-2/PI3K/Akt axis—and clinical correlates such as vulnerable coronary plaque in older patients with coronary artery disease and microvascular endotheliopathy in severe COVID-19. Finally, we review emerging anti-ageing strategies targeting the EGX, including direct oral anticoagulants, glycocalyx-mimetic and nitric-oxide-releasing biomaterials, bioinspired antithrombogenic surfaces and microbiome-based modulation, and consider their translational potential for extending cardiovascular healthspan. Full article

Shiga toxin-producing Escherichia coli (STEC) infections are a major cause of hemolytic uremic syndrome (HUS), a thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The pathogenesis of STEC-HUS is primarily driven by Shiga toxins (Stx), which induce endothelial injury, inflammation, platelet activation, and microvascular thrombosis. Hemolysis associated with thrombotic microangiopathy leads to the release of hemoglobin and free heme into the circulation. Free heme, an iron-containing molecule with potent pro-oxidative, pro-inflammatory, and cytotoxic properties, contributes to oxidative stress, endothelial dysfunction, complement activation, and further tissue injury. Oxidative stress plays a crucial role in both host and bacterial cells, influencing disease progression and the expression of bacterial virulence factors, including Shiga toxin. N-acetyl-L-cysteine (NAC), a precursor of glutathione (GSH) and a well-established antioxidant, has attracted attention as a potential adjunctive therapeutic agent due to its antioxidant, anti-inflammatory, antiplatelet, and cytoprotective properties. In addition, NAC may influence iron- and heme-mediated oxidative damage and improve erythrocyte resistance to oxidative stress. This review summarizes current knowledge regarding the roles of oxidative stress and free heme in STEC-HUS and examines the mechanistic rationale and current evidence supporting NAC as a potential adjunctive strategy. The available evidence remains largely indirect and preclinical; therefore, the potential role of NAC in STEC-HUS should be considered hypothesis-generating and requires further investigation in clinical studies. Full article

Background/Objectives: Biological ageing is accompanied by progressive alterations in mitochondrial metabolism, microvascular function, and thermoregulation. These processes collectively influence tissue heat production and dissipation, reflecting integrated metabolic, vascular, and thermoregulatory activity measurable at the physiological level. Passive microwave radiometry (MWR) provides a non-invasive, radiation-free method for detecting deep-tissue bioenergy emissions, complementing surface infrared thermography. To evaluate a thermophysiological Bioenergetic Index (BEI), derived from deep-tissue microwave emission, surface temperature, and their spatial and deep–surface relationships, as a candidate age-referenced thermophysiological marker associated with chronological ageing. Methods: Breast thermophysiology measurements from 36,391 women aged 20–80 years were analysed using data collected during routine clinical assessments. Supervised machine-learning models were trained exclusively on thermal features, with chronological age used only as the prediction target. Model performance was assessed using mean absolute error (MAE), root mean square error (RMSE), and coefficient of determination (R²). In addition, data were aggregated into 5-year age bins to evaluate population-level ageing trajectories. Results: At the individual level, models predicted chronological age with MAE ≈ 3.5 years, RMSE ≈ 5.4 years, and R² ≈ 0.76. Aggregation into 5-year age bins revealed a robust nonlinear ageing trajectory characterised by midlife decline and late-life stabilisation. The increased correspondence at the grouped level reflects reconstruction of the population-level ageing trajectory rather than improved individual-level prediction accuracy, as averaging reduces inter-individual variability. Conclusions: These findings demonstrate a strong ageing-related signal in female breast thermophysiology and support thermophysiology as a candidate age-referenced physiological marker, pending longitudinal and outcome-based validation. The present analysis is cross-sectional and requires longitudinal validation before diagnostic or prognostic interpretation. Full article

Coronary artery vasospasm (CAV) is a transient, reversible constriction of the epicardial coronary arteries that reduces coronary blood flow and may cause myocardial ischemia. Despite its clinical significance, CAV remains underdiagnosed and can present as chest pain, acute coronary syndrome, malignant arrhythmias or sudden cardiac death. Vasospasm may occur in both angiographically normal coronary arteries and at sites of pre-existing atherosclerotic stenosis. The pathophysiology of CAV is multifactorial and involves vascular smooth muscle cells (VSMCs) hyperreactivity, endothelial dysfunction, chronic inflammation and autonomic dysregulation. VSMCs contraction is mediated by phosphorylation of the myosin light chain (MLC) through calcium (Ca²⁺)/calmodulin-dependent myosin light chain kinase (MLCK), while relaxation is regulated by myosin light chain phosphatase (MLCP). Increased intracellular Ca²⁺ levels and enhanced Ca²⁺ sensitivity contribute to excessive vasoconstriction. Rho-kinase (ROCK) plays a pivotal role in sustained vasospasm by inhibiting MLCP, thereby promoting prolonged smooth muscle contraction. Endothelial dysfunction contributes to CAV by disrupting normal vascular tone regulation, largely as a result of decreased nitric oxide (NO) mediated vasodilation. Chronic low-grade inflammation and oxidative stress exacerbate both endothelial dysfunction and VSMCs contraction. Understanding these molecular mechanisms is essential for identifying novel therapeutic targets. Emerging treatment strategies, including ROCK inhibitors, endothelin receptor antagonists and anti-inflammatory agents, may improve outcomes in patients with refractory CAV. Full article

Chronic coronary syndromes (CCSs) are increasingly recognized as complex immunometabolic vascular disorders in which coronary microvascular dysfunction (CMD), persistent low-grade inflammation, oxidative stress, and maladaptive cellular remodeling contribute to ischemic symptoms and adverse outcomes beyond epicardial stenosis. CMD represents a heterogeneous condition comprising both functional and structural endotypes and constitutes a major determinant of myocardial ischemia, heart failure progression, and adverse cardiovascular outcomes, even in the absence of obstructive coronary artery disease. Emerging evidence indicates that immunometabolic reprogramming of endothelial cells, vascular smooth muscle cells, and immune cells sustains microvascular dysfunction in CCSs. Metabolic shifts toward glycolysis, mitochondrial dysfunction, redox imbalance, and dysregulated lipid metabolism promote chronic inflammatory activation within the coronary microenvironment. Convergent mitochondrial stress (including NAD⁺ decline) and redox injury promote endothelial senescence and increase susceptibility to regulated cell death, progressively limiting vasodilatory reserve and predisposing to microvascular rarefaction. Pyroptosis and ferroptosis-like lipid peroxidation further exacerbate endothelial barrier disruption and inflammatory amplification. In parallel, inflammasome activation, iron-dependent lipid peroxidation, impaired autophagy, and endoplasmic reticulum stress form interconnected molecular networks that amplify vascular injury through self-reinforcing mechanisms. This narrative review integrates mechanistic and translational evidence linking immunometabolic dysregulation, mitochondrial stress, thromboinflammatory signaling, endothelial senescence, and regulated cell death to distinct CMD endotypes. We propose a systems-level framework in which coronary microvascular dysfunction is conceptualized as an immunometabolic vascular network disorder, with reduced coronary flow reserve (CFR)—often termed myocardial flow reserve (MFR) in PET studies—emerging as the integrative functional endpoint of these interacting molecular perturbations and a robust predictor of major cardiovascular events. Full article