Explore the vast range of titles available.

INTRODUCTION Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODS We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6‐Tg(Thy1‐APPSwDutIowa)BWevn/Mmjax (Tg‐SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTS Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9‐ to 10‐month‐old Tg‐SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load. DISCUSSION These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD. Highlights Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model. Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD. Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.

Corona virus disease 2019 (COVID‐19) causes symptoms from multiple organs after infection by severe acute respiratory syndrome corona virus 2 (SARS CoV‐2). They range from early, low blood oxygen levels (hypoxemia) without breathlessness (“silent hypoxia”), delirium, rashes, and loss of smell (anosmia), to persisting chest pain, muscle weakness and ‐pain, fatigue, confusion, memory problems and difficulty to concentrate (“brain fog”), mood changes, and unexpected onset of hypertension or diabetes. SARS CoV‐2 affects the microcirculation, causing endothelial cell swelling and damage (endotheliitis), microscopic blood clots (microthrombosis), capillary congestion, and damage to pericytes that are integral to capillary integrity and barrier function, tissue repair (angiogenesis), and scar formation. Similar to other instances of critical illness, COVID‐19 is also associated with elevated cytokine levels in the systemic circulation. This review examines how capillary damage and inflammation may contribute to these acute and persisting COVID‐19 symptoms by interfering with blood and tissue oxygenation and with brain function. Undetectable by current diagnostic methods, capillary flow disturbances limit oxygen diffusion exchange in lungs and tissue and may therefore cause hypoxemia and tissue hypoxia. The review analyzes the combined effects of COVID‐19‐related capillary damage, pre‐existing microvascular changes, and upstream vascular tone on tissue oxygenation in key organs. It identifies a vicious cycle, as infection‐ and hypoxia‐related inflammation cause capillary function to deteriorate, which in turn accelerates hypoxia‐related inflammation and tissue damage. Finally, the review addresses the effects of low oxygen and high cytokine levels in brain tissue on neurotransmitter synthesis and mood. Methods to assess capillary functions in human organs and therapeutic means to protect capillary functions and stimulate capillary bed repair may prove important for the individualized management of COVID‐19 patients and targeted rehabilitation strategies. COVID‐19‐related microvascular damage and inflammation may cause tissue hypoxia via transit‐time effects and disturb neurotransmitter synthesis in the brain. The duration of COVID‐19 symptoms and the long‐term health effects of SARS‐CoV‐2 infection may rely on whether disease‐related capillary damage is reversible.

Capillary dysfunction has been implicated in a series of life- threatening vascular diseases characterized by pericyte and endothelial cell (EC) degeneration. However, the molecular profiles that govern the heterogeneity of pericytes have not been fully elucidated. Single-cell RNA sequencing was conducted on oxygen-induced proliferative retinopathy (OIR) model. Bioinformatics analysis was conducted to identify specific pericytes involved in capillary dysfunction. qRT-PCRs and western blots were conducted to detect Col1a1 expression pattern during capillary dysfunction. Matrigel co-culture assays, PI staining, and JC-1 staining was conducted to determine the role of Col1a1 in pericyte biology. IB4 and NG2 staining was conducted to determine the role of Col1a1 in capillary dysfunction. We constructed an atlas of > 76,000 single-cell transcriptomes from 4 mouse retinas, which could be annotated to 10 distinct retinal cell types. Using the sub-clustering analysis, we further characterized retinal pericytes into 3 different subpopulations. Notably, GO and KEGG pathway analysis demonstrated that pericyte sub-population 2 was identified to be vulnerable to retinal capillary dysfunction. Based on the single-cell sequencing results, Col1a1 was identified as a marker gene of pericyte sub-population 2 and a promising therapeutic target for capillary dysfunction. Col1a1 was abundantly expressed in pericytes and its expression was obviously upregulated in OIR retinas. Col1a1 silencing could retard the recruitment of pericytes toward endothelial cells and aggravated hypoxia-induced pericyte apoptosis . Col1a1 silencing could reduce the size of neovascular area and avascular area in OIR retinas and suppressed pericyte-myofibroblast transition and endothelial-mesenchymal transition. Moreover, Col1a1 expression was up-regulated in the aqueous humor of the patients with proliferative diabetic retinopathy (PDR) or retinopathy of prematurity (ROP) and up-regulated in the proliferative membranes of PDR patients. These findings enhance the understanding of the complexity and heterogeneity of retinal cells and have important implications for future treatment of capillary dysfunction.

Alzheimer’s disease (AD) is currently considered the major cause of cognitive impairment in older adults. This explains the close attention to the issue of AD research. The pathomorphological basis of the disease is a neurodegenerative process, the early stages of which are formed in the hippocampus and the morphofunctionally deep parts of the temporal lobes of the brain closely related to it. Several hypotheses have been advanced concerning the causes of neurodegeneration: the amyloid hypothesis, the calcium homeostasis impairment hypothesis, the inflammatory hypothesis, and the prion hypothesis. However, these hypotheses cannot explain the early stages of the pathogenesis of neurodegenerative diseases, in particular Alzheimer’s disease. This health problem requires further comprehensive study of available data, as well as additional investigations to determine the nature of such a process. In this review, the data on microcirculatory disorders in the capillaries of the hippocampus and mediobasal structures of the temporal lobes of the brain, which may be an initiating factor that triggers neurodegenerative events, are analyzed.

Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.

Background Post-stroke cognitive impairment (PSCI) is common. However, the underlying pathophysiology remains largely unknown. Understanding the role of microvascular changes and finding markers that can predict PSCI, could be a first step towards better screening and management of PSCI. Capillary dysfunction is a pathological feature of cerebral small vessel disease and may play a role in the mechanisms underlying PSCI. Extracellular vesicles (EVs) are secreted from cells and may act as disease biomarkers. We aim to investigate the role of capillary dysfunction in PSCI and the associations between EV characteristics and cognitive function one year after acute ischemic stroke (AIS) and transient ischemic attack (TIA). Methods The ENIGMA study is a single-centre prospective clinical observational study conducted at Aarhus University Hospital, Denmark. Consecutive patients with AIS and TIA are included and followed for one year with follow-up visits at three and 12 months. An MRI is performed at 24 h and 12 months follow-up. EV characteristics will be characterised from blood samples drawn at 24 h and three months follow-up. Cognitive function is assessed three and 12 months after AIS and TIA using the Repeatable Battery for the Assessment of Neuropsychological Status. Discussion Using novel imaging and molecular biological techniques the ENIGMA study will provide new knowledge about the vascular contributions to cognitive decline and dementia. Trial registration The study is retrospectively registered as an ongoing observational study at ClinicalTrials.gov with the identifier NCT06257823.

In acute ischemic stroke, critical hypoperfusion is a frequent cause of hypoxic tissue injury: As cerebral blood flow (CBF) falls below the ischemic threshold of 20 mL/100 mL/min, neurological symptoms develop and hypoxic tissue injury evolves within minutes or hours unless the oxygen supply is restored. But is ischemia the only hemodynamic source of hypoxic tissue injury? Reanalyses of the equations we traditionally use to describe the relation between CBF and tissue oxygenation suggest that capillary flow patterns are crucial for the efficient extraction of oxygen: without close capillary flow control, “functional shunts” tend to form and some of the blood’s oxygen content in effect becomes inaccessible to tissue. This phenomenon raises several questions: Are there in fact two hemodynamic causes of tissue hypoxia: Limited blood supply (ischemia) and limited oxygen extraction due to capillary dysfunction ? If so, how do we distinguish the two, experimentally and in patients? Do flow-metabolism coupling mechanisms adjust CBF to optimize tissue oxygenation when capillary dysfunction impairs oxygen extraction downstream? Cardiovascular risk factors such as age, hypertension, diabetes, hypercholesterolemia, and smoking increase the risk of both stroke and dementia. The capillary dysfunction phenomenon therefore forces us to consider whether changes in capillary morphology or blood rheology may play a role in the etiology of some stroke subtypes and in Alzheimer’s disease. Here, we discuss whether certain disease characteristics suggest capillary dysfunction rather than primary flow-limiting vascular pathology and how capillary dysfunction may be imaged and managed.

Increased epithelial and endothelial permeability, along with dysregulated inflammatory responses, are key aspects of acute respiratory distress syndrome (ARDS) pathophysiology, which not only impact the lungs but also contribute to detrimental organ crosstalk with distant organs, ultimately leading to multiple organ dysfunction syndrome (MODS)—the primary cause of morbidity and mortality in patients with lung injury (LI) and ARDS. It is predominantly manifested by hypoxemic respiratory failure and bilateral pulmonary infiltrates, which cannot be fully attributed to cardiac failure or hypervolemia, but rather to alveolo-capillary barrier dysfunction, dysregulated systemic and pulmonary inflammation, immune system abnormalities, and mechanical stimuli-related responses. However, these pathological features are not uniform among patients with ARDS, as distinct subphenotypes with unique biological, clinical, physiological, and radiographic characteristics have been increasingly recognized in recent decades. The severity of ARDS, clinical outcomes, mortality, and efficacy of applied therapeutic measures appear significant depending on the respective phenotype. Acknowledging the heterogeneity of ARDS and defining distinct subphenotypes could significantly modify therapeutic strategies, enabling more precise and targeted treatments. To address these issues, a comprehensive literature search was conducted in PubMed using predefined keywords related to ARDS pathophysiology, subphenotypes, and personalized therapeutic approaches. Optimizing the identification and characterization of discrete ARDS subphenotypes—based on clinical, biological, physiological, and radiographic criteria—will deepen our understanding of ARDS pathophysiology, promote targeted recruitment in prospective clinical studies to define patient clusters with heterogeneous therapeutic responses, and support the shift toward individualized treatment strategies.

To investigate mechanisms underlying the effects of Da-Cheng-Qi decoction (DCQD) on severe acute pancreatitis (SAP) capillary leakage syndrome. In this study, a SAP rat model was established using retrograde perfusion of 5% sodium taurocholate into the biliopancreatic duct. The study included three randomized groups: control, SAP (modeling), and DCQD (via gavage at 2 h pre-modeling and 2 and 4 h post-modeling). HPLC was used to analyzed major components of DCQD. Pathological changes and capillary permeability in the rat pancreatic tissues were examined. mRNA levels of claudin 5, occludin, zonula occludin-1 (ZO-1), and junctional adhesion molecules (JAM-C) were assessed using qRT-PCR. Tight junction-associated protein expression was evaluated using immunofluorescence and Western blot analyses. Human umbilical vein endothelial cells (HUVECs) were used to investigate the mechanism m of DCQD. Serum levels of amylase, TNF-α, IL-1β, IL-2, and IL-6 were higher in the SAP group compared to the DCQD group ( < 0.05). DCQD treatment significantly attenuated rat pancreas damage ( < 0.05) and reduced tissue capillary permeability compared to the SAP group ( < 0.05). Claudin 5, occludin, and ZO-1 expression in the rat tissues was upregulated, but JAM-C was downregulated by DCQD treatment ( < 0.05). HUVEC permeability was improved by DCQD in a dose-time-dependent manner compared to the SAP group ( < 0.05). DCQD also upregulated claudin 5, occludin, and ZO-1 expression ( < 0.05). DCQD can improve capillary permeability in both and models of SAP by upregulating expression of claudin 5, occludin, and ZO-1, but not JAM-C.