Testicular disorders, including male infertility and hypogonadism, are increasingly prevalent and current diagnostic tools have important limitations. The testicular microcirculation underpins testicular function. Ultrasound localisation microscopy (ULM) enables super-resolution mapping of microvascular structure and flow at clinically relevant organ depth. Prospective case-control study of ULM-assessed testicular activity in men and rodents using clinical and research ultrasound systems. Study 1 compared healthy men (n = 10) with hypogonadotrophic hypogonadism (HH) (n = 9). Study 2 included men with HH receiving testosterone (n = 11), gonadotrophins (n = 9), or no treatment (n = 12). Study 3 assessed 12-month fertility treatment response in HH (n = 7). A rodent pubertal-blockade model was also studied (n = 5). ULM markers discriminated HH from controls (vessel density p < 0.01; diameter p = 0.01; tortuosity p < 0.01) and correlated with testosterone (r = 0.53-0.67, p < 0.05) and inhibin B (r = -0.61, p < 0.01). Vessel density, diameter, area and flow-related index were reduced in azoospermia (p < 0.01). ULM distinguished HH treatment groups (vessel density p < 0.001; diameter p < 0.05), with density and diameter correlating with testosterone (r = 0.69, 0.62; p < 0.001) and inhibin B (r = 0.64, 0.65; p < 0.001). Vessel density (p < 0.001) and diameter (p < 0.01) were reduced in azoospermia irrespective of treatment. During fertility therapy, ULM parameters increased (p < 0.05) and detected testicular activation earlier than volume or inhibin B. In rodents, pubertal development showed dynamic microvascular remodelling driven by testis growth. ULM provides a treatment-responsive, biologically grounded biomarker of testicular function enabling patient stratification, early detection of therapeutic response, and potential for both refinement of clinical decision-making in HH, and application within other testicular disorders. MRC, NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility, Diabetes UK, BBSRC, MRC, Imperial Private Healthcare Clinical Research Fellowship Scheme, NWLP Research Grant.
Diabetic retinopathy and diabetic nephropathy are major microvascular complications of type 2 diabetes mellitus and may progress silently before clinical detection. Plasma glycated CD59 has been proposed as a marker linked to complement-mediated endothelial injury. This study assessed plasma glycated CD59 levels in type 2 diabetic patients with retinopathy, nephropathy, and combined microvascular complications. This cross-sectional observational study included 420 patients with type 2 diabetes mellitus. Participants were divided into four groups: diabetes without microvascular complications (n = 110), diabetic retinopathy alone (n = 105), diabetic nephropathy alone (n = 95), and combined diabetic retinopathy with nephropathy (n = 110). Clinical history, diabetes duration, fasting plasma glucose, glycated haemoglobin, serum creatinine, estimated glomerular filtration rate, urine albumin-creatinine ratio, and plasma glycated CD59 were assessed. Retinopathy was graded by fundus examination, and nephropathy was classified using albuminuria and renal function parameters. The mean age was 56.8 ± 9.4 years, and the mean diabetes duration was 8.9 ± 5.1 years. Plasma glycated CD59 was highest in patients with combined retinopathy and nephropathy (12.8 ± 3.6 AU/mL), followed by nephropathy alone (10.4 ± 2.9 AU/mL), retinopathy alone (9.6 ± 2.7 AU/mL), and diabetes without complications (6.2 ± 1.8 AU/mL). Plasma glycated CD59 correlated positively with glycated haemoglobin (r = 0.46, p < 0.001) and urine albumin-creatinine ratio (r = 0.52, p < 0.001), and negatively with estimated glomerular filtration rate (r = -0.41, p < 0.001). Higher levels were observed in proliferative diabetic retinopathy and macroalbuminuria. On multivariate analysis, plasma glycated CD59 remained independently associated with combined microvascular complications. Plasma glycated CD59 levels were higher in patients with type 2 diabetes who had microvascular complications, particularly in those with both diabetic retinopathy and diabetic nephropathy. These findings indicate that plasma glycated CD59 may be useful as an additional marker for assessing the burden of diabetic microvascular disease. However, as the study was cross-sectional, the results should not be interpreted as evidence of causation or prediction. Further prospective studies are needed to confirm its clinical usefulness.
We determined whether large artery stiffness (LAS) and systemic microvascular function were associated with cognitive function in older adults, and whether systemic microvascular function mediated the association between LAS and cognitive function. Older adults with diverse cardiovascular risk (n = 435, 162F) participated in this study. Estimated pulse wave velocity (ePWV) as an estimate of LAS was calculated from age and blood pressure. Skin microvascular function was assessed by acetylcholine (ACh) and sodium nitroprusside (SNP) responses using iontophoresis, and expressed as the area under the curve of each vasodilator (ACh_auc and SNP_auc, respectively). Validated cognitive tasks [Addenbrooke's Cognitive Examination Revised (ACE-R), Trail Making Test Part-A (TMT-A) and Part-B (TMT-B)] were administered to assess participants' cognitive function. One standard deviation (SD) increase in ePWV was positively associated with TMT-A [β = 0.339 (0.226, 0.467), P < 0.001] and TMT-B [β = 0.342 (0.232, 0.451), P < 0.001] after accounting for conventional cardiovascular risk factors. One SD increase in ACh_auc was also associated inversely with TMT-B after similar adjustments [β = -0.113 (-0.201, -0.024), P = 0.013]. A mediation analysis revealed that the association between ePWV and TMT-B was partially mediated by ACh_auc explaining about 3% of the total effect in the crude model, but this did not persist in the adjusted model. Increased LAS and skin microvascular dysfunction were associated with poorer cognitive function in older adults, but LAS and skin microvascular function may independently influence cognitive function in our cohort.
Cardiovascular disease (CVD) accounts for a third of all deaths, making it the leading cause of mortality globally. Coronary microvascular dysfunction (CMD) has emerged as a prominent condition in menopausal women, leading to the development of chronic coronary syndrome (CCS). Despite the significant impact on this cohort, research gaps persist which can lead to shortcomings in the delivery of care to women. CMD is more prevalent in women than men and is linked to increased risk of major adverse cardiovascular events and mortality. During the menopausal transition, there is an acceleration in vascular ageing due to hormonal shift and metabolic changes, resulting in endothelial dysfunction. A large proportion of patients with Takotsubo syndrome and heart failure with preserved ejection fraction (HFpEF) are menopausal women with CMD; however, the underlying mechanisms are not fully understood. Limited evidence of the sex-specific pathophysiology of CMD has resulted in current clinical practice relying on evidence from male-dominant or mixed cohorts. This can lead to incorrect risk stratification, treatment side effects and poor prognosis in women. In addition, there is limited research on the efficacy of diagnostic techniques addressing the sex differences in those with CMD. Tailored diagnostic thresholds and models are essential to improve prognosis in women. Further evidence is needed to bridge these knowledge gaps to tackle the sex differences, achieve sex equality in CVD research and reduce the disproportionate burden of microvascular dysfunction in menopausal women.
This study aimed to investigate retrobulbar biomechanical and microvascular changes associated with increasing axial length in myopic eyes using shear wave elastography and a quantitative vascularity index. In this prospective cross-sectional study, 99 eyes from 99 adults were classified into three groups according to axial length: <24.00 mm (Group 1), 24.00-25.99 mm (Group 2), and ≥ 26.00 mm (Group 3). All participants underwent comprehensive ophthalmologic and ultrasonographic evaluations. Shear wave elastography was used to quantify the stiffness of the optic nerve and adjacent retrobulbar fat tissue. Retrobulbar microvascularity was assessed using ultra-microangiography, with color pixel percentage measured as a vascularity index. No significant differences in tissue stiffness were observed among axial length groups (all p > 0.05). However, the vascularity index differed significantly between groups (p = 0.026) and remained independently associated with axial length after adjusting for age and sex (p = 0.041), suggesting progressive reduction in retrobulbar microvascularity, reflected by lower vascularity index values, with increasing axial elongation. Optic nerve diameter significantly decreased with increasing axial length (p = 0.010). These findings indicate that axial elongation in myopic eyes is associated with significant retrobulbar microvascular changes without corresponding alterations in tissue stiffness.
Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder in preterm infants driven by impaired vascular development, hypoxia, oxidative stress, and pathological angiogenesis. Current treatments mainly target VEGF signaling but do not directly address upstream oxidative injury. Hepcidin, a key iron-homeostasis regulator, may modulate redox balance and angiogenic activation. However, whether hepcidin is reduced in ROP and whether supplementation mitigates hypoxia-induced oxidative stress and abnormal angiogenesis in retinal endothelial cells remain unclear. To investigate the effects of hepcidin on human retinal microvascular endothelial cells (hRMECs) under oxidative stress and assess its translational potential in ROP. Clinical data were collected from 35 preterm infants with gestational age <36 weeks, including 24 non-ROP controls and 11 ROP infants. Gestational age, birth weight, ROP stage, and serum hepcidin were analyzed. hRMECs were exposed to 1% O2 to establish a hypoxia model. Cell viability, VEGFA and HIF-1α mRNA expression, secreted VEGFA, intracellular reactive oxygen species (ROS), transcriptomic changes, and tube formation were evaluated. Hepcidin was added under hypoxia to assess its effects on oxidative stress and angiogenic activation. Infants with ROP had lower gestational age and birth weight than controls, and gestational age differed across ROP stage groups. Serum hepcidin-related signals were numerically lower in ROP infants, but no significant stage-dependent decrease was observed. In hRMECs, 1% O2 altered cell viability, upregulated VEGFA and HIF-1α mRNA, increased secreted VEGFA, and promoted ROS accumulation, confirming a hypoxia-induced endothelial stress model. Transcriptomic analysis suggested that hepcidin affected hypoxia-responsive metabolic pathways, including cysteine and methionine, selenocompound, and tryptophan metabolism. Functional validation showed that hepcidin reduced VEGFA at transcript and secreted protein levels, decreased intracellular ROS, and suppressed hypoxia-induced tube formation by reducing junction points, branch points, and total tube length. This study provides preliminary clinical and experimental evidence supporting a potential role of hepcidin-related signaling in ROP. Although the clinical findings are exploratory, the in vitro results indicate that hepcidin can attenuate hypoxia-induced oxidative stress and pathological angiogenic activation in retinal endothelial cells. Hepcidin may represent a biologically relevant pathway and potential candidate for further biomarker and therapeutic research in ROP.
Microvascular decompression (MVD) is the first-line surgical treatment for trigeminal neuralgia (TN). However, some patients experience recurrence despite achieving immediate pain relief after MVD. This study aimed to identify the risk factors for TN recurrence and to develop a predictive nomogram model. We enrolled patients with TN who achieved immediate pain relief after MVD with at least 2 years of follow-up. Logistic regression analysis was used to explore the risk factors of long-term pain recurrence, based on the results of multivariate logistic regression analysis, a nomogram model for predicting pain recurrence was developed. Receiver operating characteristic curve (ROC) was used to analyze the prediction efficiency of the nomogram model, and calibration curve was used to analyze the accuracy of the nomogram model. Eventually, 264 patients were included in this study, during a mean follow-up of 43.06 ± 16.99 months, 23 patients experienced pain recurrence. Regression analysis suggested that younger age, longer pain duration, and atypical pain were the independent risk factors for long-term pain recurrence. The nomogram demonstrated excellent discriminatory power, with an area under the curve (AUC) of 0.958. The calibration curve analysis indicated good agreement between the predicted and observed probabilities. Favorable long-term outcomes could be achieved in TN patients with immediate pain relief after MVD, patients with younger age, longer pain duration and atypical pain may be at higher risk for pain recurrence.
Diabetic silent myocardial ischemia (DSMI) represents a clinically underappreciated yet life-threatening cardiovascular complication in which impaired myocardial perfusion occurs without recognisable symptoms. Two converging pathological axes underlie this phenotype: coronary microvascular dysfunction and neurocardiac signalling disruption. Chronic hyperglycaemia drives oxidative stress, advanced glycation end-product (AGE) accumulation, and mitochondrial dysfunction in endothelial and smooth-muscle cells, collectively impairing nitric oxide (NO) bioavailability, coronary flow reserve, and capillary integrity. Simultaneously, diabetic peripheral and autonomic neuropathy attenuates nociceptive transmission and disrupts neurovascular coupling, blunting the perception of ischaemic pain. At the molecular level, dysregulated insulin receptor (INSR), angiotensin II type 1 receptor (AT1R), toll-like receptor 4 (TLR4), AMP-activated protein kinase (AMPK), and transient receptor potential (TRP) channel signalling converge to perpetuate endothelial injury, vascular inflammation, and neural dysfunction. Critically, emerging evidence implicates mitochondrial reactive oxygen species (mtROS) overproduction, impaired mitochondrial biogenesis, and altered mitochondrial dynamics as shared mechanistic nodes linking both axes. This review synthesises current mechanistic knowledge within a novel unified framework, proposes candidate biomarkers-including urinary 8-OHdG, NT-proBNP, heart rate variability indices, and coronary flow reserve by cardiac PET/CMR-and identifies actionable therapeutic targets, including mitochondria-directed antioxidants (MitoQ, SS-31), SGLT2 inhibitors, GLP-1 receptor agonists, TLR4 antagonists, and TRPV1 modulators. Testable mechanistic hypotheses and directions for future translational research are proposed to accelerate early diagnosis and disease-modifying intervention in high-risk diabetic patients.
Microvascular invasion (MVI) is a key predictor of recurrence in hepatocellular carcinoma (HCC), but it is diagnosed pathologically after surgery. We aimed to develop and validate a simplified preoperative nomogram using routine markers and tumor burden score (TBS). This retrospective study included 512 patients with HCC who underwent radical hepatectomy between June 2018 and 2023 (309 MVI-negative and 203 MVI-positive). Predictors were selected by univariate analysis and least absolute shrinkage and selection operator regression. Multivariable logistic regression was used to construct the model. Discrimination, calibration, and clinical utility were assessed using the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. An interactive dynamic nomogram was developed from the final model. The nomogram incorporated dichotomized aspartate aminotransferase (≥29.5 U/L), platelet count (≥127.5 × 109/L), and alpha-fetoprotein (≥400 ng/ml), and TBS modeled as a continuous variable with restricted cubic splines. The model showed good discrimination (AUC = 0.720), good agreement between predicted and observed probabilities, and meaningful net benefit when the threshold probability exceeded 20%. This simplified dynamic nomogram provides a practical noninvasive tool for preoperative MVI risk assessment and may support individualized decision-making in patients with HCC.
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Microvascular endothelial cell-derived extracellular vesicles (EVs) mediate local intercellular communication relevant to wound healing and inflammation, yet their proteomic cargo and functional properties remain poorly characterized. Here, EVs were isolated from human microvascular endothelial cells (HMEC-1) by standard ultracentrifugation (UC Bulk) or ultracentrifugation combined with size exclusion chromatography (UC+SEC) and characterized by nanoparticle tracking analysis, immunoblotting, cryogenic electron microscopy, and label-free mass spectrometry. UC+SEC achieved a 77-fold improvement in particle-to-protein ratio with 70-93% depletion of serum and extracellular matrix contaminants while preserving canonical EV markers (ALIX, CD9). Mass spectrometry identified 673 proteins in UC+SEC versus 336 in UC Bulk, with both preparations enriched in wound healing, hemostasis, and angiogenesis pathways. Despite dramatic purity differences, both isolation methods produced functionally comparable EVs that significantly enhanced dermal fibroblast wound closure. Functional assays on primary human dermal microvascular endothelial cells (HDMECs) revealed that HMEC-1-derived EVs exert inflammation-dependent dual effects on TNF-α pre-treated endothelium: upregulating VCAM-1 expression while simultaneously preserving VE-cadherin-mediated junction integrity. These effects were strictly inflammatory-dependent, with no detectable activity on healthy endothelial cells. This research uncovers a paradoxical phenotype in which microvascular endothelial EVs enhance immune cell recruitment signals while protecting barrier function exclusively under inflammatory conditions, suggesting a regulatory mechanism that may contribute to vascular homeostasis during inflammatory challenges.
Advanced hepatocellular carcinoma (HCC) presents a range of presentations and responses to immunotherapy. We sought to determine the effects of Atez/Bev in patients with advanced HCC and various prognostic factors. We analyzed 183 patients with advanced HCC who received Atez/Bev and targeted the response patterns of 517 intrahepatic tumors and 88 extrahepatic tumors, organized by poor prognostic indicators: extrahepatic metastasis (EHM), microvascular invasion (MVI), and large intrahepatic tumors (≥5 cm). The median progression-free survival (PFS) and overall survival (OS) were recorded at 8.0 months and 22.6 months, respectively, with an objective response rate of 19.7%. Response patterns differed significantly for large intrahepatic tumors (≥5 cm): these tumors progressed more slowly than smaller tumors, accompanied by a similar incidence of new lesions and target lesion progression. The correlation between PFS and OS varied notably between patients with large tumors and those without, with correlation coefficients of 0.662 (95% CI: 0.559-0.764) and 0.475 (95% CI: 0.326-0.624), respectively. Intrahepatic lesions displayed homogenous responses (correlation coefficient = 0.682), while the correlation between intrahepatic and extrahepatic responses was weaker (correlation coefficient = 0.474). Tumors with MVI varied their response patterns according to their associated vascular invasion, although MVI did not influence survival. EHM affected PFS and OS, while tumor size only influenced OS. Large intrahepatic tumors treated with Atez/Bev demonstrate prolonged stability, incomplete responses, and worse survival. The differing correlations between PFS and OS based on tumor size have significant implications for the design of clinical trials. This may indicate a potential advantage in incorporating locoregional interventions for treating large tumors in HCC strategies. This study looked at how a combination treatment called atezolizumab plus bevacizumab (Atez/Bev) works in patients with advanced hepatocellular carcinoma (HCC), a type of liver cancer. People with this cancer often respond differently to treatment depending on factors like the size, location, and spread of their tumors. We studied 183 patients with advanced HCC who received Atez/Bev. In total, we analyzed 517 liver tumors (inside the liver) and 88 tumors that had spread outside the liver. We paid special attention to patients who had poorer outcomes due to cancer spreading beyond the liver (extrahepatic metastasis), cancer invading small blood vessels (microvascular invasion), and large tumors (5 cm or larger). We found that the median time before the cancer worsened (progression-free survival, or PFS) was 8.0 months, and the median overall survival (OS) was 22.6 months. About 20% of patients showed a clear positive response to the treatment. Interestingly, larger tumors inside the liver tended to progress more slowly than smaller tumors, even though new tumors appeared at a similar rate. Tumors inside the liver often behaved similarly, while tumors outside the liver showed more variable responses. Microvascular invasion influenced how tumors responded to treatment, but did not seem to affect survival. In contrast, extrahepatic spread negatively affected both PFS and OS, while tumor size mainly affected OS. Importantly, we found that the relationship between PFS and OS depended on tumor size. These insights could help improve the design of future clinical trials for advanced HCC.
Type 2 diabetes (T2D) is a risk factor for the progression of liver disease, particularly relating to metabolic dysfunction-associated steatotic liver disease (MASLD), and consequent major adverse liver outcomes (MALO). Given that diabetic neuropathy reflects advanced metabolic and microvascular injury, we investigated whether somatic and autonomic neuropathy in T2D is associated with MALO. In this retrospective cohort study using a large, federated health research network (TriNetX), adults with T2D were stratified into (i) diabetes alone, without coding of neuropathy, (ii) diabetes with peripheral neuropathy coding, (iii) diabetes with autonomic neuropathy coding, and (iv) diabetes with combined peripheral and autonomic neuropathy coding. Propensity score matching was performed to balance demographic, metabolic, and comorbidity profiles. The primary outcome was incident MALO, defined as hepatic decompensation, portal hypertension/stable varices, hepatocellular carcinoma, liver failure, or liver transplantation. Secondary outcomes included individual MALO endpoints, major adverse cardiovascular events (MACE) and all-cause mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs). After matching, a clear gradient was evident between the increased risk of MALO and the presence of neuropathy: peripheral neuropathy and risk of MALO (HR 1.95 [95% CI 1.85, 2.05]), autonomic neuropathy (HR 2.62 [2.52, 2.72]) and combined neuropathy (HR 3.21 [3.03, 3.41]). Associations were consistent across individual MALO endpoints, irrespective of obesity status, and remained significant following temporal washout analyses. Neuropathy also conferred greater risk for MALO compared to other microvascular complications (vs. retinopathy; 2.21 [2.05, 2.39]). Diabetic neuropathy is associated with an elevated risk of MALO in T2D. Autonomic, and to a lesser extent peripheral, neuropathy identifies a particularly high-risk phenotype, supporting neuropathic burden as a surrogate marker, and potential driver, of advanced systemic metabolic injury and progressive liver risk.
Diabetic retinopathy (DR) is a leading cause of vision loss worldwide and is increasingly recognized as a complex neurovascular disease characterized by early neuroinflammation, neurodegeneration, and microvascular dysfunction. Current therapies primarily target late-stage vascular complications and do not adequately address the upstream mechanisms involved in DR onset and progression. Minocycline, a second-generation semisynthetic tetracycline with high lipophilicity, has emerged as a promising therapeutic candidate because of its pleiotropic pharmacological effects beyond antimicrobial activity. Accumulating experimental evidence indicates that minocycline exerts anti-inflammatory, anti-apoptotic, mitochondrial-protective, and potentially epigenetic regulatory effects in diabetic retinal tissues and cellular models. Mechanistically, minocycline suppresses microglial activation, attenuates pro-inflammatory signaling, stabilizes the blood-retinal barrier, preserves mitochondrial function, inhibits matrix metalloproteinase activity, and has been associated with changes in histone acetylation and methylation under diabetic conditions. These actions may help preserve retinal neurovascular integrity and reduce neuronal and microvascular injury in experimental DR models. Despite promising preclinical findings, clinical evidence remains limited. Early-phase clinical studies indicate that oral minocycline is generally well tolerated; however, its efficacy has not been established in adequately powered clinical trials. This review summarizes the pharmacological properties of minocycline, critically examines its molecular mechanisms in DR pathogenesis, and discusses current clinical evidence, translational challenges, and future research directions. Although available data support further investigation of minocycline for DR, additional preclinical and clinical studies are needed to determine its therapeutic efficacy and clinical applicability.
Diabetic neuropathy (DN) is a prevalent microvascular complication of diabetes mellitus, characterized by hyperalgesia and allodynia that severely impair quality of life. Current treatment approaches do not provide adequate relief, largely due to the multifactorial nature of disease pathogenesis. Growing evidence indicates that dysregulation of multiple ion channel families is a central mechanism underlying sensory neuron hyperexcitability and chronic pain in DN. This review comprehensively discusses the roles of major ion channel families, including voltage-gated sodium (Naᵥ), calcium (Caᵥ), and potassium (Kᵥ) channels, transient receptor potential (TRP) channels, purinergic receptors (P2X/P2Y), and mechanosensitive PIEZO (PIEZO 1 and PIEZO 2) channels, in sensory transmission and pain modulation. Their dysregulation, induced by chronic hyperglycemia and oxidative stress, promotes ectopic firing, altered calcium homeostasis, and glial activation, sustaining nociceptive hypersensitivity. The review further evaluates current and emerging ion channel-targeted therapeutic approaches, highlighting mechanistic insights, translational challenges, and future research directions. Recent research highlights multi-target and combination strategies, such as Naᵥ1.8 inhibition with KCNQ activation or concurrent blockade of TRPV1 and P2X3, as promising avenues offering synergistic analgesic benefits and disease-modifying potential. Advances in nanocarrier-based delivery, gene modulation, and patient-specific electrophysiological profiling further enhance translational prospects. Ultimately, the therapeutic landscape of PDN is shifting from single-channel blockade toward integrated approaches that modulate excitability, inflammation, and metabolic stress concurrently. Ion channels thus represent not only crucial mediators of PDN pathophysiology but also versatile therapeutic targets whose selective and combinatorial modulation may transform the management of diabetic neuropathic pain. See also the graphical abstract(Fig. 1).
Microvascular rarefaction is a predominant pathological hallmark of chronic kidney disease (CKD), functioning simultaneously as a catalyst and consequence of progressive renal compromise. Although endothelial senescence constitutes a cardinal mediator of microvascular attrition in CKD, its upstream regulatory mechanism remains elusive. Here, using integrated single-cell/spatial transcriptomics, decellularized scaffold modeling, diverse murine CKD models, vascular ultrasonography, and tissue-clearing-enabled 3D imaging, we identify fibrillin-1 (FBN1), a core constituent of the fibrogenic niche, as an architect of a pro-senescent microenvironment that directly triggers endothelial senescence. Mechanistically, FBN1 upregulates the transcription factor ZEB1, which binds to the EDN1 promoter to enhance endothelin-1 (ET-1) transcription, thereby activating the ET-1/β-catenin signaling axis to execute cellular senescence. This cascade is abolished by ZEB1 knockdown, ET-1 receptor antagonism, or β-catenin inhibition. Importantly, tubule-specific Fbn1 deletion suppresses endothelial senescence, attenuates capillary rarefaction, and ameliorates renal function across CKD models. Our study unveils the FBN1/ZEB1/ET-1/β-catenin axis as a spatially organized signaling pathway linking to endothelial senescence, demonstrating how matrix-embedded components actively perpetuate pathogenesis by orchestrating stable pathological microenvironments. These findings provide a conceptual framework for CKD-associated vascular deterioration and highlight microenvironmental reprogramming as a therapeutic paradigm.
Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation. In the central nervous system (CNS), most ferroptosis research has focused on neurons and glial cells, whereas the vulnerability of brain microvascular endothelial cells (BMECs) and its consequences for blood-brain barrier (BBB) integrity remain less clearly defined. Because BMECs form the vascular interface between the circulation and the brain parenchyma, ferroptotic injury in this cell population may represent an immunovascular mechanism through which endothelial redox stress is translated into barrier dysfunction and neuroinflammatory amplification. In this review, we summarize molecular pathways that may promote or restrain BMEC ferroptosis, including iron handling, antioxidant defense mediated by the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) axis and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, lipid peroxidation, and junctional remodeling. We then discuss how ferroptosis-associated endothelial injury may contribute to BBB leakage, damage-associated molecular pattern release, innate immune sensing, leukocyte recruitment, glial activation, and self-amplifying inflammatory feedback at the neurovascular interface. We organize the available literature according to the strength and cellular specificity of evidence, separating BMEC-specific findings, BBB-focused in vivo studies, indirect CNS evidence, and mechanistic analogies from non-CNS endothelial systems. Finally, we evaluate disease-specific evidence in ischemic stroke and selected neurodegenerative or inflammatory conditions, together with therapeutic strategies, BMEC-targeting considerations, candidate clinical biomarkers, and translational barriers for modulating endothelial ferroptosis. This review frames endothelial ferroptosis as a promising but incompletely established immunovascular link between BBB dysfunction and neuroinflammation, and highlights the need for BMEC-specific models, human BBB systems, endothelial ferroptosis biomarkers, biomarker-guided monitoring, BMEC-targeted delivery approaches, and careful evaluation of the physiological risks of systemic or prolonged ferroptosis blockade.
Diabetes is associated with oxidative stress, systemic immune dysregulation and chronic low-grade inflammation, which contributes to a wide spectrum of microvascular and macrovascular complications. Efferocytosis, the phagocytic clearance of apoptotic cells by macrophages and dendritic cells, is essential for inflammation resolution and tissue repair. Defective efferocytosis has been increasingly implicated in the progression of diabetes and several of its major complications, including atherosclerosis, nephropathy, retinopathy, impaired wound healing, and osteoporosis. This narrative review is prepared through a focused literature search of studies investigating efferocytosis in diabetes, elucidates how its disruption contributes to the progression of diabetic complications, and further highlight emerging therapeutic strategies aimed at regulating efferocytosis. This paper is expected to provide direction and outlook for the research on efferocytosis and diabetes. Efferocytosis regulation involves a coordinated cascade of find-me signals, engulfment receptors, intracellular cytoskeletal remodeling, and metabolic reprogramming. This review summarizes the key molecular changes of defective efferocytosis and pathological changes in diabetic complications. Importantly, emerging preclinical studies have demonstrated that restoring efferocytosis ameliorate inflammation, promote tissue regeneration, and interrupt the progression of diabetic complications. Efferocytosis not only illuminates fundamental aspects of immune regulation but also opens up new therapeutic possibilities. As the field continues to evolve, integrating efferocytosis-based interventions into the broader therapeutic landscape of diabetes may represent a paradigm shift in the management of its chronic complications.
Long COVID refers to multisystem symptoms that begin within 3 months of COVID-19 infection and persist for at least 2 months. To this day, Long COVID remains a challenging clinical entity and a substantial global health burden, with cardiovascular sequelae representing a prominent component. Patients frequently report a range of symptoms including chest pain, palpitations, fatigue, and exercise intolerance. This mini review aims to synthesize current evidence on the symptom profiles, underlying mechanisms, and clinical management of Long COVID-related cardiovascular complications. We conducted a targeted narrative literature search of PubMed/MEDLINE, Web of Science, Scopus, Embase, and Google Scholar for articles published up to January 2026 using combinations of "Long COVID," "post-acute sequelae of SARS-CoV-2 infection," "cardiovascular," "myocarditis," "endothelial dysfunction," "microvascular injury," "dysautonomia," "vaccination," and "SARS-CoV-2 variants." Original studies, systematic reviews, meta-analyses, clinical guidance documents, and selected mechanistic studies were prioritized, whereas non-peer-reviewed preprints and single case reports were included only when they provided unique mechanistic or hypothesis-generating information. Eligibility was based on cardiovascular relevance to Long COVID; studies without post-acute or cardiovascular relevance were excluded. The evidence indicates that cardiovascular Long COVID is heterogeneous and multifactorial, involving viral persistence, immune dysregulation, endothelial dysfunction, microvascular injury with hypercoagulability, autonomic nervous system dysregulation, and risk modification by acute disease severity, vaccination status, and SARS-CoV-2 variant period. Current management strategies remain primarily symptom-based, with emphasis on cardiovascular risk assessment, mechanism-informed phenotyping, graded rehabilitation, dysautonomia-directed treatment, and multidisciplinary follow-up. Cardiovascular Long COVID is a heterogeneous burden driven by interacting mechanisms. Current evidence supports subgroup-based risk stratification and mechanism-informed management, while future studies should standardize endpoints and evaluate mechanism-targeted interventions.
This study aimed to develop a novel rat model of Chronic subdural hematoma (CSDH) that better recapitulates human pathophysiological mechanisms, enhancing clinical relevance for translational research. The CSDH model was established using a triple-component system comprising allogeneic venous blood, cerebrospinal fluid (CSF), and cerebral microvascular endothelial cells (bEnd.3). Stereotaxic surgery involved subdural injection of the mixture (200 µL) via a microsyringe pump, followed by two additional injections at 72-hour intervals. Subsequently, systematic validation of the model was conducted. Data were analyzed using GraphPad Prism 9. All procedures adhered to ARRIVE guidelines and ethical approval. The CSF-blood co-culture system generated mechanically stable, heterotypically remodeled clots with ultrastructural features mirroring human CSDH membranes. The optimized CSDH model exhibited crescent-shaped subdural hematomas on MRI, temporal concordance in VEGF/Ang-2/MMP-9 expression peaks (day 14), and progressive neurological recovery, closely recapitulating clinical-pathological progression. This study establishes a reproducible CSDH model combining progressive subdural injection and stereotaxic localization to recapitulate chronic hematoma dynamics, validated through quantitative morphological, inflammatory, and functional profiling, thereby providing a clinically faithful platform for mechanistic and therapeutic investigation.