Search Results (505)

Diabetic retinopathy (DR) is a common cause of vision loss in diabetes, and it often progresses without early symptoms. DR reflects injury of the retinal neurovascular unit (NVU), which includes neurons, Müller glia, astrocytes, endothelial cells, pericytes, and immune cells. Chronic hyperglycemia drives oxidative stress, advanced glycation end products–receptor for advanced glycation end products (AGE–RAGE) signaling, mitochondrial injury, and low-grade inflammation. These changes disrupt endothelial junctions, promote leukostasis, weaken pericyte support, increase basement membrane thickening, and lead to capillary dropout and hypoxia. Hypoxia-related signaling increases anti-vascular endothelial growth factor (VEGF) activity, which raises vascular leakage and supports neovascular disease. Glial stress and microglial activation add cytokines and reactive oxygen species, and neural dysfunction can appear early and can weaken neurovascular coupling. Modern diabetes care changes the short-term risk landscape because potent therapies can lower HbA1c quickly. Large and rapid HbA1c reductions can trigger early worsening of diabetic retinopathy (EWDR), mainly in patients with high baseline HbA1c and moderate-to-severe baseline DR. Semaglutide’s retinopathy complication signal in SUSTAIN-6 fits an EWDR-like pattern that tracks with rapid glycemic improvement in vulnerable eyes. In parallel, surgery adds acute stress, inflammation, glucose swings, hemodynamic shifts, and medication interruptions. These factors can worsen microvascular instability during recovery. Current perioperative guidelines and regulatory recommendations describe glucose targets and medication safety considerations, including preoperative interruption of SGLT2 inhibitors to reduce euglycemic ketoacidosis risk; however, the retina-specific implications of these measures remain indirect. This review summarizes current evidence linking NVU biology, EWDR risk, and perioperative diabetes-related factors. It discusses how these factors may interact in patients with diabetes and how they may influence retinal outcomes. The review is intended to synthesize current evidence and mechanistic interpretations rather than to provide formal clinical practice recommendations. Full article

Intracranial atherosclerosis (ICAS) is a distinct, inflammation-dominant vasculopathy and a leading cause of global stroke morbidity. Unlike extracranial atherosclerosis (ECAS), which often utilizes compensatory positive remodeling to maintain patency, ICAS is characterized by a unique architecture and a localized antioxidant gap that favor maladaptive negative remodeling. We critically analyze the molecular cascade initiated by the breakdown of the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) and the Krüppel-like factor 2/4 (KLF2/4) mechanotransduction axis, which triggers endothelial nitric oxide synthase (eNOS) uncoupling and establishes a state of chronic inflammation. This environment facilitates the subendothelial lipid retention of oxidized low-density lipoprotein (oxLDL), a process exacerbated by the intracranial deficiency of Apolipoprotein A-I (ApoA-I) and impaired glymphatic clearance. Crucially, we evaluate how these metabolic and mechanical insults drive vascular smooth muscle cell (VSMC) phenotypic switching; the transdifferentiation of contractile VSMCs into macrophage-like foam cells accounts for up to 60% of the plaque’s lipid-laden pool and destabilizes the fibrous cap. This vascular failure directly compromises the neurovascular unit (NVU), leading to pericyte dropout and blood–brain barrier breakdown. Beyond environmental stressors, we highlight the ring finger protein 213 (RNF213) variant as a critical genetic determinant of this susceptibility. Shifting the clinical paradigm from simple luminal narrowing toward the identification of the vulnerable plaque, we discuss how High-Resolution Vessel Wall Imaging (HR-VWI) and microRNA biomarkers can identify unstable lesions. By integrating these molecular and imaging signatures, we propose a precision medicine framework centered on the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NVU to effectively mitigate the high residual recurrence risk that persists under conventional therapy. Full article

Diabetic retinopathy (DR) is more than a capillary disorder. Diabetes affects neurons, glial cells, vascular cells, and immune signals within the retinal neurovascular unit (NVU). Retinal neurovascular coupling (NVC) is a useful functional marker of NVU integrity because it reflects the rise in local blood flow that follows neural activity. Many human flicker-light studies report smaller vessel dilation or weaker flow responses in diabetes. This finding can appear even in patients without clear fundus lesions. When NVC is reduced, retinal tissue may receive less oxygen. Lower oxygen delivery can raise oxidative stress and promote inflammation. These changes can then worsen vascular injury. This review describes key NVC pathways and diabetes-related NVU changes in Müller glia, astrocytes, microglia, pericytes, and endothelial cells. The review highlights sympathetic activation as a common stress signal. Pain, anxiety, perioperative stress, and sleep loss can increase sympathetic activity and circulating catecholamines. In the diabetic retina, vascular reserve is often limited. Under these conditions, catecholamines can increase mural cell constriction, reduce nitric oxide (NO)-dependent relaxation, and increase endothelial activation and barrier strain. These effects can shift the baseline state of glial and immune cells and further weaken NVC. The review also summarizes translational tools that can test these links. These tools include heart rate variability, standardized NVC protocols with diameter and flow measures, and retinal organoid and organ-on-a-chip platforms with controlled adrenergic exposure. The review discusses perioperative care packages that reduce stress responses, protect sleep, and manage glucose as practical ways to support retinal microcirculation. More longitudinal human studies are still needed. Retina-specific perioperative endpoints are also needed to clarify causality and to guide intervention trials. Full article

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and can lead to severe visual impairment. Based on disease severity, DR is classified into no clinically apparent diabetic retinopathy (NDR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). Although nearly all retinal cell types are involved in DR progression, the dominant cell populations and their pathophysiological changes at each stage remain unclear. By integrating bulk and single-cell transcriptomic data from human and mouse retinas, this study revealed the following: (1) In the NDR stage, photoreceptors exhibit significant changes in ribosomal pathways. (2) In the NPDR stage, endothelial cells and pericytes show marked transcriptional alterations, accompanied by enhanced LAMININ signaling in cell-cell communication. (3) At the PDR stage, neural and glial cells are extensively involved in disease progression, with notable changes in ANGPTL signaling. Additionally, this study observed DR-specific subtypes of endothelial cells and pericytes and potentially identifies gene signatures in macroglia cells that correlate with disease duration. The altered expression of several key genes in early diabetic retina was confirmed by qPCR. These findings may offer a comprehensive view of the cellular and molecular landscape underlying DR and may suggest potential targets. Full article

Alcohol (ethanol, an intoxicating agent in all alcoholic beverages) is the most widely consumed beverage in the United States and is a leading risk-factor for cerebrovascular diseases. Although neurons, microglia, and astrocytes have been moderately studied for their responsiveness to ethanol, the brain vasculature is minimally explored and is emerging as a key player in the interplay between neuroinflammation, cerebrovascular disease, and alcohol use disorder (AUD). The blood–brain barrier (BBB), a critical regulator of brain homeostasis, relies on the coordinated function of various cellular and molecular components to maintain its immune-privileged status. Emerging evidence indicates that chronic ethanol exposure disrupts BBB function, contributes to neurovascular dysfunction, and increases brain permeability to peripheral immune factors. This review introduces the endothelial cells (ECs) that make up the BBB and provides a brief overview of the junction proteins and transporters that assist with EC function and EC interactions with other cells of the neurovascular unit, including pericytes, smooth muscle cells, and perivascular macrophages and glial cells. In addition, this review highlights ethanol’s effects on ECs and the cells that interact with them. Lastly, given the mounting evidence on gender differences in AUD and the supporting sex differences in ethanol consumption in preclinical models, this review discusses the discovered sex differences in EC-specific genes and identifies open questions such as the influence of sex-dependent differences, genetic factors, and their interactions with ethanol on EC function. Taken together, a deeper understanding of how ethanol disrupts EC structure and function will advance therapeutic strategies to mitigate neuroinflammation and related pathologies associated with chronic ethanol exposure. Full article

The blood–brain barrier (BBB) is a vital protective structure that prevents harmful substances in the blood from entering the central nervous system while maintaining homeostasis. Its dysfunction can lead to significant pathological changes and contribute to various neurological disorders, such as stroke and neurodegenerative diseases. BBB damage of varying degrees is observed in nearly all cerebrovascular diseases, yet the specific mechanisms remain largely unclear. Growing evidence indicates that ferroptosis—an iron-dependent, lipid peroxidation-driven form of regulated cell death—is a major pathway contributing to BBB disruption. Ferroptosis affects multiple key brain cell types, including endothelial cells, glial cells, pericytes, and neurons, potentially leading to BBB dysfunction in cerebrovascular diseases. This article explores the role of ferroptosis in different types of cerebrovascular diseases and its effects on various cells. It covers the latest research in this area and highlights the potential benefits of targeting ferroptosis, including protecting the blood–brain barrier, reducing neuroinflammation, and protecting neurons. Full article

Chronic alcohol exposure disrupts blood–brain barrier (BBB) integrity and promotes neuroinflammation, with P2X7 receptor (P2X7R) signaling playing a critical role. Our prior work in male mice linked P2X7R inhibition to reduced extracellular adenosine triphosphate (eATP) release, modulated extracellular vesicle (EV) cargo, and attenuated neuroinflammation in chronic intermittent ethanol (CIE)-exposed mice. However, sex-specific roles of P2X7R signaling and EV-mediated mechanisms in alcohol-induced neuroinflammation remain unclear. Male and female mice were exposed to ethanol vapor for three weeks and treated with Brilliant Blue G (BBG), a P2X7R inhibitor. Compared to their respective CIE-unexposed controls, brain gene expression of tumor necrosis factor–α (Tnf-α), interleukin-1 beta (Il-1b), interleukin-6 (Il-6), monocyte chemoattractant protein-1 (Mcp-1), and Fas ligand (Fasl) significantly increased in CIE-exposed males, while only Il-1b increased in females. P2X7R inhibition significantly reduced these cytokines. Pericyte immunostaining was decreased by CIE (indicating BBB injury) in male mice only and was restored by P2X7R inhibition with no difference between groups in females. Occludin staining (another BBB marker) did not differ between the treatment groups in male and female animals. Circulating cytokines (Macrophage inflammatory protein-1 alpha (MIP-1α), tumor necrosis factor–α (TNF-α), interleukin-1 beta (IL-1β), and interleukin-27 subunit p28/interleukin-30 (IL-27p28/IL-30) were significantly elevated in CIE-exposed males but not in females, with BBG treatment reducing cytokines in males. Circulating eATP, P2X7Rs, P-glycoprotein (P-gp), EVs, and EV-mtDNA, which we identified in our previous study, were increased in both sexes and partially decreased by P2X7R blockade. Spatial memory was impaired by CIE exposure in males but not females, and this deficit was reversed by BBG treatment. Our findings reveal sex differences in CIE-induced circulating cytokines, neuroinflammation, and memory impairment, with a stronger response in males. However, other markers of cell injury associated with CIE exposure were upregulated in both sexes; P2X7R inhibition effectively mitigated these effects, highlighting the functional relevance of targeting the P2X7R in alcohol-induced injury. Full article

Ischemic stroke is a leading cause of disability worldwide, marked by profound disruption of the neurovascular unit (NVU), a dynamic grouping of neurons, astrocytes, cerebral endothelial cells (CECs), microglia, pericytes, and oligodendrocytes. While acute stroke interventions such as tissue plasminogen activator and endovascular thrombectomy address reperfusion, they fail to engage the prolonged and cell-specific processes critical for recovery. Extracellular vesicles (EVs), membrane-bound carriers of proteins, lipids, and nucleic acids, have emerged as key modulators of intercellular communication within the NVU. This review synthesizes current evidence on NVU-derived EVs as both regulators and effectors of post-stroke pathology and repair. We highlight the phase-specific roles of EVs in modulating blood–brain barrier (BBB) integrity, thrombosis, angiogenesis, neurogenesis, oligodendrogenesis, synaptic plasticity, and neuroinflammation. This review places special emphasis on how EV cargo reflects the state of their parent cells and how EV-mediated crosstalk orchestrates coordinated neurorestorative responses. We further discuss the dual nature of EVs, their therapeutic potential for stroke, and the methodological challenges impeding clinical translation, including isolation standardization, cell-specific targeting, and regulatory barriers. Thus, adherence to minimal information for studies of extracellular vesicles (MISEV) guidelines is essential to ensure rigor, reproducibility, and transparency. When combined with temporal and cellular specificity, NVU-derived EVs may represent a biomimetic platform for promoting durable recovery in stroke patients. Full article

Background: Traumatic brain injury (TBI) frequently leads to long-term neurological deficits. Recent research also implicates cellular senescence—a state of permanent cell cycle arrest driven by DNA damage—as a key contributor to neuroinflammation and cognitive decline. This study investigates the cell-type specificity of senescence within glial and vascular cells of the neurovascular unit (NVU) following experimental TBI in a rat model. Methods: Rats underwent various TBI scenarios, including single severe TBI (sTBI), single mild TBI (mTBI), repetitive mild TBI (rmTBI) and repetitive sham-operated control (rSham). Twenty-four hours or four weeks later, brains were harvested and brain sections were co-stained for γH2AX and cell type-specific markers. Immunofluorescence microscopy was used to comprehensively assess senescence in both glial and vascular cells of the NVU, specifically astrocytes, microglia, endothelial cells, and pericytes. Results: We observed acute increased astrocyte senescence in sTBI samples and microglial senescence in mTBI and sTBI samples in the neocortex, while endothelial cell senescence was significantly elevated in the neocortex of the sTBI group after four weeks. Pericytes did not exhibit significant signs of senescence at either time point. Conclusion: These findings demonstrate differential γH2AX labelling of NVU components following TBI, suggesting that vulnerability to TBI-induced senescence can be specific both to the cell type and the time after the injury. This has implications on therapies targeting senescent cells for mitigating the long-term consequences of TBI. Full article

We studied the expression of connexin 43 (Cx43) and pannexin 1 (PANX1) in different cellular populations of the kidneys of diabetic mice and diabetic and non-diabetic patients, to evaluate their role as potential therapeutic targets in diabetic kidney disease (DKD). A combination of a low dose of streptozotocin and a high-fat diet (HFD) was used to induce a type 2 diabetes model (DM2) in mice. Kidney tissues from diabetic (n = 9) and control patients (n = 11) who underwent nephrectomy were collected. Tissues from mice and humans were processed for double immunofluorescence, using antibodies against Cx43, phosphorylated Cx43 (pCx43) or PANX1 and markers for specific cell populations: endothelium (CD31/PECAM1); pericytes/mesangium (PDGFRB); podocytes (nephrin/synaptopodin); proximal tubules and collecting ducts (aquaporin 2). The results showed a significant decrease in the expression of pCx43 in PDGFRB-immunoreactive mesangium in diabetic patients compared to the control group (p < 0.0001). This contrasted with an increase in pCx43 in pericytes of diabetic mice (p = 0.1). However, we found a general decrease in Cx43 protein expression in diabetic mouse kidneys (p < 0.05). We also found a decrease in the expression of PANX1 in endothelial cells of diabetic patients (p < 0.05) and a significant increase in PANX1 expression in cells expressing PDGFRB (p < 0.05). Expression of PANX1 in endothelium (r = −0.50; p < 0.05) and pCx43 in the mesangium (r = −0.65; p < 0.01) correlated negatively with the percentage of sclerotic glomeruli. The expression and activation of Cx43 and the expression of PANX1 are altered in distinct populations of renal cells during long-term type 2 diabetes mellitus, especially cells of the vascular wall. This may indicate their role in the pathophysiological processes of DKD. Therefore, connexin and pannexin channels could be considered as possible therapeutic targets in the prevention and treatment of diabetic kidney disease. Full article

Fate-mapping studies have challenged the longstanding view of the adult mammalian heart as a post-mitotic organ, suggesting limited cardiomyocyte renewal. This has spurred efforts to determine whether selected cardiac stromal cells have regenerative potential; however, their contribution to cardiac regeneration has been found to be minimal compared with that of cardiomyocyte proliferation. Despite this, transplantation of some cardiac stromal cell populations has shown therapeutic potential through paracrine signalling. The identity of the paracrine-active stromal cell populations remains unclear due to overlapping characteristics with other cardiac stromal cell populations, such as fibroblasts, mesenchymal cells, and pericytes. This study sought to clarify the transcriptional identity and heterogeneity of adult mouse cardiac stromal cells by developing a cardiac collagenase–trypsin protocol and comparing it to the established method for isolating cardiosphere-derived cells (CDCs). This novel protocol resulted in a higher cell yield and shorter expansion time, and the resulting cells showed superior survival under serum starvation compared to commercially acquired cardiac fibroblasts (CFs). Single-cell qRT-PCR analysis revealed that collagenase–trypsin cells (CTs) and CDCs share similar gene expression profiles, distinct from those of CFs. Notably, CTs exhibited higher expression of Tcf21 and lower expression of Tbx5, suggesting an epicardial-derived fibroblast phenotype, whereas Tbx5 was enriched in CDCs and CFs, reflecting heterogeneity within the cardiac fibroblast compartment. This study offers insights into the complex identity of cardiac stromal cells and concludes that CTs closely resemble CDCs but can be generated more rapidly, making them a robust and efficient source of paracrine-active cardiac stromal cells. Full article

Glioblastoma (GBM) remains one of the most lethal brain tumors, largely due to the resilience and plasticity of glioblastoma stem cells (GSCs), which drive tumor growth, recurrence, and resistance to conventional therapies. A key mechanism underlying their aggressiveness is transdifferentiation, whereby GSCs acquire endothelial- and pericyte-like phenotypes, promoting neovascularization and remodeling the tumor microenvironment to sustain malignancy. Conventional treatments often fail to eliminate these resilient populations, highlighting the need for innovative targeted strategies. Chimeric antigen receptor (CAR)-based immunotherapies offer a targeted strategy to specifically eliminate GSCs and interfere with their role in promoting tumor vascularization and suppressing immune responses. This review aims to provide a comprehensive overview of the molecular mechanisms driving GSC transdifferentiation and to summarize the current landscape of CAR-T therapies developed to target these cells. By integrating knowledge of GSC biology with advances in CAR-T-based interventions, this work highlights the potential of next-generation immunotherapies to overcome therapeutic resistance, limit tumor recurrence, and improve clinical outcomes in GBM. Full article

The increasing production and accumulation of plastic waste, coupled with insufficient recycling practices, contribute to the growing presence of plastic in the environment. Nanoplastic particles are of particular concern, as they pose greater (health and environmental) risks and exhibit wider dispersion compared to macroplastics. The blood–brain barrier may be exposed to nanoplastics present in the blood, which could affect its functionality or even pass through and damage the central nervous system. This study examined the effects of polystyrene (PS) nanoparticles with different chemical surface modifications (pristine, carboxylated, aminated) and sizes (50 nm and 100 nm) on cells of the neurovascular unit (NVU): human brain endothelial cells, astrocytes, and pericytes. Results indicated that only high concentrations of nanoparticles (100 μg/mL and 300 μg/mL) applied for 48 h decreased cell viability and barrier integrity significantly. Specifically, 50 nm carboxylated PS particles reduced barrier integrity and altered tight junction gene expression substantially. Fluorescent labelling of the investigated particles enabled to confirm their uptake by all tested cell types of the NVU, but also highlighted that the labelling changes the particles’ properties. Furthermore, cell culture medium-dependent particle agglomeration and increase of size were inversely correlated with cellular internalisation, which has to be considered for future risk assessments. Full article

Adipose tissue includes various cell types beyond the typical adipocytes. The stromal vascular fraction (SVF) contains mesenchymal stem cells (MSCs), pericytes, and endothelial cells, which can be isolated from adipose tissue by mechanical and enzymatic methods. The composition of the SVF is heterogeneous, and donor factors such as sex, age, body mass index (BMI), and harvesting site are associated with variations in cellular composition and viability. The expression of specific surface markers, which determine the immunophenotype of the cells, can also vary. In this study, we investigated the effects of donor age, BMI, and harvesting site on cell yield, viability, and size. Our results showed that BMI significantly influenced cell yield and size, with overweight and obese donors yielding more cells than normal-weight donors. Additionally, cells isolated from the adipose tissue of the thighs/legs were larger than those from other areas. Flow cytometry showed considerable variability in SVF composition among donors. These results emphasize that SVF donor characteristics have a significant impact on cell yield, viability, and cell size, with the immunophenotype being highly donor-dependent. Understanding these factors is crucial for optimizing cell yield and defining populations for therapeutic applications of SVF cells. Full article

Acute lung injury (ALI) pathogenesis is intricately linked to microvascular permeability. Soluble guanylate cyclase (sGC) is prominently expressed in the vascular system, playing a central role in vascular function. In contrast, its expression and function diminish notably during the progression of ALI, indicating sGC’s potential significance as a pivotal modulator in the pathological processes of ALI. Nonetheless, the precise localization of sGC within lung tissue and its distinct mechanism in maintaining vascular homeostasis remain unclear. Furthermore, there is a necessity for a pharmacological agent capable of consistently activating sGC for the treatment of ALI. A novel sGC stimulator, sGC003, was engineered through structural modification of Riociguat. In a mouse model of ALI, sGC003 exhibited superior sGC activation and more potent anti-inflammatory effects relative to Riociguat. It also exhibited superior efficacy in improving respiratory function and reducing pulmonary edema. Through single-cell RNA sequencing and immunofluorescence co-localization analysis, we confirmed predominant expression of soluble guanylate cyclase in pericytes. The sGC stimulators were found to modulate the LPS-induced pericyte transcriptome reprogramming via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. Differential gene expression analysis categorized pericytes into nine distinct subgroups, which were sequentially activated during vascular development, inflammation, and myofibrosis. Pseudotime analysis revealed that sGC003 more effectively suppressed the myofibroblast differentiation of pericytes compared to Riociguat. In conclusion, sGC003 mitigates ALI-induced pulmonary inflammation by modulating pericyte differentiation, particularly in preserving microvascular integrity outstanding performance. Its exceptional efficacy suggests that it could potentially serve as a safer and more efficient option as a novel sGC stimulant in the future. Full article