Microcirculatory Disturbances Research Articles

Hirayama Disease in a Young Male: A Case Report

Hirayama disease is a rare benign neurological disease that affects the anterior horn of the spinal cord at C5 to T1, mainly at C7 and C8 due to imbalance growth between the vertebral column and the dura mater leading to microcirculatory disturbances in the anterior portion of the spinal cord due to overstretched cord, especially during flexion of the neck causing unilateral or rarely asymmetrically bilateral upper limb weakness and muscle wasting.It is a case of a 21-year-old boy presented with weaknesses in his left hand and forearm for 2 years which aggravates during cold weather and flexion of the neck. A plain x-ray of the neck and MRI of the cervical spine were conducted which show the features of Hirayama disease.

Salvianolic acid B improves the microcirculation in a mouse model of sepsis through a mechanism involving the platelet receptor CD226.

Salvianolic acid B (SalB) demonstrates diverse clinical applications, particularly in cardiovascular and cerebral protection. This study primarily investigated the effects of SalB on sepsis. The model of sepsis via caecal ligation puncture (CLP) was established in male C57BL/6 mice. Therapeutic effects of SalB on hepatic and pulmonary injury, inflammatory responses and microcirculatory disturbances in sepsis were evaluated. Platelet aggregation and adhesion were measured via flow cytometry and an adhesion test. After overexpression of platelet-related activating molecules by 293T cells, the efficient binding of SalB and platelet CD226 molecules was further evaluated. Finally, neutralizing antibody experiments were used to assess the mechanism of SalB in alleviating the progression of sepsis. SalB mitigated hepatic and pulmonary impairments, reduced inflammatory cytokine levels and enhanced mesenteric microvascular blood flow in septic mice. SalB enhanced CLP-induced reduction of platelet count and platelet pressure cumulative volume. SalB reduced platelet adhesion to endothelial cells and platelet aggregation to leukocytes. A high binding efficiency was observed between SalB and the platelet adhesion molecule CD226. Ex vivo, interactions between SalB and platelets from CD226-knockout mice were markedly decreased. In vivo administration of CD226 neutralizing antibodies significantly delayed disease progression and enhanced mesenteric microcirculation in septic mice. In our murine model of sepsis, treatment with SalB improved the microcirculatory disturbance and hindered the progression of sepsis by inhibiting platelet CD226 function. Our results suggest SalB is a promising therapeutic approach to the treatment of sepsis.

Microcirculatory Perfusion Disturbances During Veno-Arterial Extracorporeal Membrane Oxygenation: ASystematic Review.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used in case of potentially reversible cardiac failure and restores systemic hemodynamics. However, whether this is followed by improvement of microcirculatory perfusion is unknown. Moreover, critically ill patients have possible pre-existing microcirculatory perfusion disturbances. Therefore, this review provides an overview of alterations in sublingual microcirculatory perfusion in critically ill adult patients receiving VA-ECMO support. Pubmed, Embase (Ovid), Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched according to PRISMA guidelines. Studies reporting sublingual microcirculatory perfusion measurements in adult patients supported by VA-ECMO were included. Outcome parameters included small vessel density (SVD), perfused vessel density (PVD), perfused small vessel density (PSVD), proportion of perfused vessels (PPV), microvascular flow index (MFI) and the heterogeneity index (HI). The protocol was registered at PROSPERO (CRD42021243930). The search identified 1215 studies of which 11 were included. Cardiogenic shock was the most common indication for VA-ECMO (n=8). Three studies report increased PSVD, PPV, and MFI 24 hours after initiation of ECMO compared to pre-ECMO. Nonetheless, microcirculatory perfusion stabilized thereafter. Four out of four studies showed higher PSVD and PPV in survivors compared to non-survivors. Over time, survivors showed recovery of microcirculatory perfusion within hours of initiation of ECMO, whereas this was absent in non-survivors. Notwithstanding the limited sample, VA-ECMO seems to improve microcirculatory perfusion shortly after initiation of ECMO, especially in survivors. Further research in larger cohorts is needed to clarify the longitudinal effects of ECMO on microcirculatory perfusion.

COMPARATIVE STUDY OF MICROCIRCULATION PARAMETERS IN THE LOWER EXTREMITIES OF PATIENTS WITH TYPE 2 DIABETES DEPENDING ON BODY WEIGHT

This study focuses on the comparative analysis of microcirculation parameters in the lower extremities of patients with type 2 diabetes mellitus (T2DM), considering their body weight. Microcirculation disturbances are common in diabetic patients and are significantly influenced by obesity. The study evaluates how body weight impacts blood flow and tissue perfusion in the lower extremities. Results indicate that patients with higher body weight exhibit more pronounced microcirculation disorders, which can exacerbate complications such as diabetic foot syndrome. These findings highlight the importance of weight management in improving microvascular health in T2DM patients.

Quantification of Video Sequences of the Microcirculation: A Comparison Between Automated Analysis Using Analysis Manager and Manual Analysis Using Capillary Mapper.

Microcirculatory disturbances can contribute to organ dysfunction in patients undergoing major surgeries and critical illness. Incident dark field imaging (CytoCam, Braedius Medical BV, Huizen, Netherlands) provides direct visualization of the microcirculation. To utilize this method in daily clinical practice, automated image analysis is essential. This study aims to compare the automated analysis of recorded microcirculation video sequences using CytoCamTools V2 Analysis Manager (Braedius Medical BV) with established manual analysis using Capillary Mapper (Version 1.4.5, University Hospital Münster, Germany) as reference method. Sublingual microcirculation video sequences were recorded in patients undergoing laparotomy at four time points (before surgery, 2 and 6 h after surgery, and on the first postoperative day) using incident dark field imaging. Agreement between automated and manual analysis of total vessel density (TVD), perfused vessel density (PVD), and proportion of perfused vessels (PPV) was compared using intraclass correlation (ICC) and Bland-Altman method. A total of 336 videos from 30 patients were analyzed. The ICC between the two measurement methods was 0.13 for TVD, 0.14 for PVD, and 0.16 for PPV. Bland-Altman analysis showed mean differences (95% limits of agreement) of 10.46 mm/mm2 (-1.73-22.65 mm/mm2) for TVD, 8.25 mm/mm2 (-9.88-26.39 mm/mm2) for PVD, and - 3.96% (-59.58%-51.65%) for PPV. Automated microcirculatory analysis using the Analysis Manager did not show clinically acceptable agreement with manual analysis using Capillary Mapper. Consequently, automated video analysis using the Analysis Manager does not appear to be a suitable approach. ClinicalTrials.gov identifier: DRKS00020264.

Magnetic resonance imaging features and stroke etiology of ischemic stroke in essential thrombocythemia

BackgroundVarious essential thrombocythemia (ET)-related stroke mechanisms have been proposed, including microcirculatory disturbance due to coagulopathy, vasculitis, and embolism due to thrombus formation in large vessels. However, the stroke mechanism in ET remains largely unexplored. The purpose of this study was to evaluate magnetic resonance image (MRI) features of ischemic stroke in ET and determine the potential stroke mechanism. MethodsWe retrospectively collected data from 21 acute ischemic stroke patients with ET who were admitted to two stroke centers between 2010 and 2023. ET was diagnosed according to the World Health Organization criteria. We evaluated MRI features including the diffusion-weighted image (DWI) lesion pattern, and the presence of hemorrhagic transformation and intracranial artery steno-occlusive lesion, as well as other etiological workup results. ResultsOf 21 patients, 20 exhibited multiple ischemic lesions on DWI, mainly within a single vascular territory. Cortical infarcts were observed in 19 patients. Hemorrhagic transformation occurred in 15 patients. Additionally, 15 patients had intracranial steno-occlusive arteries, which regressed to normal in 11 patients during follow-up. Out of all patients, only 2 had potential causes of stroke other than ET (1 with atrial fibrillation and 1 with intracranial atherosclerotic stenosis). The remaining 19 patients had ET as the only identified potential cause. ConclusionsMRI features, including DWI lesion pattern in ischemic stroke patients with ET, suggested embolic etiology despite the absence of major embolic sources. Intra-arterial thrombus appears to be part of the stroke mechanism related to ET and may contribute to ischemic stroke in ET.

Paeoniae radix alba improved intestinal mucosal microcirculation disturbance by regulating lncRNA MALAT1/HIF-1α pathway in the treatment of ulcerative colitis

BackgroundMicrocirculatory problems in the intestinal mucosa are the primary cause of ulcerative colitis (UC). Although UC is commonly treated with paeoniae radix alba (PRA), its exact mechanism of action is unclear. PurposeTo examine how PRA affects UC induced by dextran sulfate sodium (DSS) and the mechanism of its effects. MethodsThe primary active components of PRA were identified using high-performance liquid chromatography (HPLC), and network pharmacology techniques were used to predict the possible targets of action and signaling pathways in treatment for UC. A model of UC was established in vivo using rats, and a PRA intervention was performed. The amounts of cytokines in the colonic tissues and serum were measured using enzyme-linked immunosorbent assay (ELISA). The permeability of the intestinal mucosa was measured using a fluorescein isothiocyanate (FITC)-dextran assay and western blot. A PeriCam PSI system was used to view the microcirculation of the intestinal mucosa, and immunohistochemistry and immunofluorescence stains were used to detect angiogenesis. An electron microscope was used to observe the damage to the endothelium of the colon. Western blot and immunohistochemistry analyses were used to evaluate the protein expression of hypoxia-inducible factor-1 alpha (HIF-1α) in colon tissues, and qRT-PCR was used to assess the lncRNA expression of MALAT1. ResultsHPLC identified 10 main active components of PRA, and the network pharmacology results showed that the treatment of UC with PRA was associated with the HIF-1 signaling pathway. The results of animal experiments revealed that PRA significantly improved the pathological damage to the colon and the microcirculatory issues in the intestinal mucosa. PRA also inhibited colonic endothelial cell damage and angiogenesis, which may be related to the inhibition of the increased expression of lncRNA MALAT1 and HIF-1α in colon tissues. ConclusionsThe anti-UC effect of PRA by improving intestinal mucosal microcirculatory disorders was first reported in this study. PRA deactivated the lncRNA MALAT1/HIF-1α pathway, inhibited endothelial angiogenesis, restored intestinal mucosal microvascular homeostasis, improved microcirculatory disorders, and alleviated the symptoms of DSS-induced UC in rats.

Lactated Ringers, albumin and mannitol as priming during cardiopulmonary bypass reduces pulmonary edema in rats compared with hydroxyethyl starch

BackgroundEndothelial disorders with edema formation and microcirculatory perfusion disturbances are common in cardiac surgery with cardiopulmonary bypass (CPB) and contribute to disturbed tissue oxygenation resulting in organ dysfunction. Albumin is protective for the endothelium and could be a useful additive to CPB circuit priming. Therefore, this study aimed to compare organ edema and microcirculatory perfusion in rats on CPB primed with lactated Ringers, albumin and mannitol (LR/albumin/mannitol) compared to 6% hydroxyethyl starch (HES).ResultsMale rats were subjected to 75 min of CPB primed with either LR/albumin/mannitol or with 6% HES. Renal and lung edema were determined by wet/dry weight ratio. Pulmonary wet/dry weight ratio was lower in rats on CPB primed with LR/albumin/mannitol compared to HES (4.77 [4.44–5.25] vs. 5.33 [5.06–6.33], p = 0.032), whereas renal wet/dry weight ratio did not differ between groups (4.57 [4.41–4.75] vs. 4.51 [4.47–4.73], p = 0.813). Cremaster microcirculatory perfusion was assessed before, during and after CPB with intravital microscopy. CPB immediately impaired microcirculatory perfusion compared to baseline (LR/albumin/mannitol: 2 [1–7] vs. 14 [12–16] vessels per recording, p = 0.008; HES: 4 [2–6] vs. 12 [10–13] vessels per recording, p = 0.037), which persisted after weaning from CPB without differences between groups (LR/albumin/mannitol: 5 [1–9] vs. HES: 1 [0–4], p = 0.926). In addition, rats on CPB primed with LR/albumin/mannitol required less fluids to reach sufficient flow rates (0.5 [0.0–5.0] mL vs. 9 [4.5–10.0], p < 0.001) and phenylephrine (20 [0–40] µg vs. 90 [40–200], p = 0.004). Circulating markers for inflammation (interleukin 6 and 10), adhesion (ICAM-1), glycocalyx shedding (syndecan-1) and renal injury (NGAL) were determined by ELISA or Luminex. Circulating interleukin-6 (16 [13–25] vs. 33 [24–51] ng/mL, p = 0.006), interleukin-10 (434 [295–782] vs. 2120 [1309–3408] pg/ml, p < 0.0001), syndecan-1 (5 [3–7] vs. 15 [11–16] ng/mL, p < 0.001) and NGAL (555 [375–1078] vs. 2200 [835–3671] ng/mL, p = 0.008) were lower in rats on CPB primed with LR/albumin/mannitol compared to HES.ConclusionCPB priming with LR, albumin and mannitol resulted in less pulmonary edema, renal injury, inflammation and glycocalyx degradation compared to 6% HES. Furthermore, it enhanced hemodynamic stability compared with HES. Further research is needed to explore the specific role of albumin as a beneficial additive in CPB priming.

Role of arterial blood glucose and interstitial fluid glucose difference in evaluating microcirculation and clinical prognosis of patients with septic shock: a prospective observational study

BackgroundMicrocirculation abnormality in septic shock is closely associated with organ dysfunction and mortality rate. It was hypothesized that the arterial blood glucose and interstitial fluid (ISF) glucose difference (GA−I) as a marker for assessing the microcirculation status can effectively evaluate the severity of microcirculation disturbance in patients with septic shock.MethodsThe present observational study enrolled patients with septic shock admitted to and treated in the intensive care unit (ICU) of a tertiary teaching hospital. The parameters reflecting organ and tissue perfusion, including lactic acid (Lac), skin mottling score, capillary refill time (CRT), venous-to-arterial carbon dioxide difference (Pv-aCO2), urine volume, central venous oxygen saturation (ScvO2) and GA−I of each enrolled patient were recorded at the time of enrollment (H0), H2, H4, H6, and H8. With ICU mortality as the primary outcome measure, the ICU mortality rate at any GA−I interval was analyzed.ResultsA total of 43 septic shock patients were included, with median sequential organ failure assessment (SOFA) scores of 10.5 (6–16), and median Acute Physiology and Chronic Health Evaluation (APACHAE) II scores of 25.7 (9–40), of whom 18 died during ICU stay. The GA−I levels were negative correlation with CRT (r = 0.369, P < 0.001), Lac (r = -0.269, P < 0.001), skin mottling score (r=-0.223, P < 0.001), and were positively associated with urine volume (r = 0.135, P < 0.05). The ICU mortality rate of patients with septic shock presenting GA−I ≤ 0.30 mmol/L and ≥ 2.14 mmol/L was significantly higher than that of patients with GA−I at 0.30–2.14 mmol/L [65.2% vs. 15.0%, odds ratio (OR) = 10.625, 95% confidence interval (CI): 2.355–47.503].ConclusionGA−I was correlated with microcirculation parameters, and with differences in survival. Future studies are needed to further explore the potential impact of GA−I on microcirculation and clinical prognosis of septic shock, and the bedside monitoring of GA−I may be beneficial for clinicians to identify high-risk patients.

Progress of heparanase in septic cardiomyopathy: A review.

Septic cardiomyopathy (SCM) is a severe complication caused by sepsis, resulting in a high mortality rate. The current understanding of the pathogenic mechanism of SCM primarily involves endocardial injury, microcirculation disturbance, mitochondrial dysfunction and fibrosis. Heparanase (HPA), an endo-β-D-glucuronidase, has been implicated in inflammation, immune response, coagulation promotion, microcirculation disturbance, mitochondrial dysfunction and fibrosis. Therefore, it was hypothesized that HPA may play an important role in the pathogenesis of SCM. The present study provides a summary of various pathophysiological changes and mechanisms behind the involvement of HPA in SCM. It also presents a novel perspective on the pathogenic mechanism, diagnosis and treatment of SCM.

Microcirculatory disturbances in acute liver failure, an ultra-structural study of immediate post mortem liver biopsies from seven patients

Microcirculatory disturbances in acute liver failure, an ultra-structural study of immediate post mortem liver biopsies from seven patients

Efficacy of Low-Molecular-Weight Heparin in the Treatment of Severe Acute Pancreatitis: A Comparative Study at a Tertiary Health Center.

Introduction Acute pancreatitis is caused by multiple factors. The disease can progress to severe acute pancreatitis (SAP) rapidly, which is a fatal condition. SAP is associated with systemic inflammatory response and disturbances in microcirculation, which are responsible for the high rate of mortality. Low-molecular-weight heparin (LMWH), apart from preventing thrombus formation, also has a property of reducing the release of cytokines and inflammatory mediators. This aids in the improvement of microcirculation of the pancreas. Materials and methods A prospective hospital-based study was conducted on 60 patients diagnosed with SAP. Patients were randomly divided into two groups: conventional treatment group (C group consisting of 30 patients) and LMWH in addition to conventional treatment (L group, consisting of 30 patients). Clinical and laboratory parameters and computed tomography (CT) scores of pancreatic necrosis (CTSPN) were compared in the two study groups. Results No significant difference (p > 0.05) was observed in the clinical and laboratory parameters and CTSPN among the two study groups at the time of admission. On initiation of treatment, the rate of improvement in symptoms and laboratory parameters were significantly higher in the L group compared with the C group (p < 0.05). Acute physiology and chronic health evaluation (APACHE) II score and development of complications were significantly lower in the L group compared with the C group (p< 0.05). CTSPN was found to be very low in the L group compared with the C group (p < 0.05). After two weeks of treatment, the recovery rate in response to treatment was observed to be higher in the L group compared to the C group, and the mortality rate was very low in the L group (p <0.05, significant). Conclusion The addition of LMWH to conventional treatment in SAP augments the effect and improves the clinical response, improving the recovery rate and decreasing mortality. LMWH is highly effective for the treatment of SAP, with a good safety profile and easy availability and without high financial burden.

Shenfu injection ameliorates endotoxemia-associated endothelial dysfunction and organ injury via inhibiting PI3K/Akt-mediated glycolysis

Ethnopharmacological relevanceMicrocirculatory dysfunction is one of the main characteristics of sepsis. Shenfu Injection (SFI) as a traditional Chinese medicine is widely applied in clinical severe conditions. Recent studies have shown that SFI has the ability to ameliorate sepsis-induced inflammation and to improve microcirculation perfusion. Aim of the studyThis study aims to investigate the underlying mechanism of SFI for ameliorating sepsis-associated endothelial dysfunction and organ injury. Materials and methodsSide-stream dark-field (SDF) imaging was used to monitor the sublingual microcirculation of septic patients treated with or without SFI. Septic mouse model was used to evaluate the effects of SFI in vivo. Metabolomics and transcriptomics were performed on endothelial cells to identify the underlying mechanism for SFI-related protective effect on endothelial cells. ResultsSFI effectively abolished the disturbance and loss of sublingual microcirculation in septic patients. Twenty septic shock patients with or without SFI administration were enrolled and the data showed that SFI significantly improved the levels of total vessel density (TVD), perfused vessel density (PVD), microvascular flow index (MFI), and the proportion of perfused vessels (PPV). The administration of SFI significantly decreased the elevated plasma levels of Angiopoietin-2 (Ang2) and Syndecan-1, which are biomarkers indicative of endothelial damage in sepsis patients. In the mouse septic model in vivo, SFI inhibited the upregulation of endothelial adhesion molecules and Ly6G + neutrophil infiltration while restored the expression of VE-Cadherin in the vasculature of the lung, kidney, and liver tissue. Additionally, SFI reduced the plasma levels of Ang2, Monocyte Chemoattractant Protein-1(MCP1), and Interleukin-6 (IL6), and alleviated liver and kidney injury in septic mice. Moreover, SFI significantly inhibited the inflammatory activation and increased permeability of endothelial cells induced by endotoxins in vitro. By performing metabolomics and transcriptomics, we identified the activation of PI3K/Akt-mediated glycolysis as the underlying mechanism for SFI-related protective effect on endothelial cells. ConclusionsOur findings revealed that SFI may improve microcirculation perfusion and endothelial function in sepsis via inhibiting PI3K/Akt-mediated glycolysis, providing theoretical evidence for the clinical application of SFI.

Hepatic microcirculatory disturbance in liver diseases: intervention with traditional Chinese medicine.

The liver, a complex parenchymal organ, possesses a distinctive microcirculatory system crucial for its physiological functions. An intricate interplay exists between hepatic microcirculatory disturbance and the manifestation of pathological features in diverse liver diseases. This review updates the main characteristics of hepatic microcirculatory disturbance, including hepatic sinusoidal capillarization, narrowing of sinusoidal space, portal hypertension, and pathological angiogenesis, as well as their formation mechanisms. It also summarized the detection methods for hepatic microcirculation. Simultaneously, we have also reviewed the characteristics of microcirculatory disturbance in diverse liver diseases such as acute liver failure, hepatic ischemia-reperfusion injury, viral hepatitis, non-alcoholic fatty liver disease, hepatic fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Finally, this review also summarizes the advancement in hepatic microcirculation attributed to traditional Chinese medicine (TCM) and its active metabolites, providing novel insights into the application of TCM in treating liver diseases.

The β2-adrenergic receptor agonist formoterol attenuates necrosis and apoptosis in the rat myocardium under experimental stress-induced cardiac injury.

Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β2-adrenergic receptor (β2-AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome. The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy. Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours. The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of β2-AR agonist formoterol (50 μg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels. Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the β2-AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress.

Microcirculatory disturbance in acute liver injury is triggered by IFNγ-CD40 axis

BackgroundAcute liver failure (ALF) is a life-threatening disorder that progresses from self-limiting acute liver injury (ALI). Microcirculatory disturbance characterized by sinusoidal hypercoagulation and subsequent massive hypoxic hepatocyte damage have been proposed to be the mechanism by which ALI deteriorates to ALF; however, the precise molecular pathway of the sinusoidal hypercoagulation remains unknown. Here, we analyzed ALI patients and mice models to uncover the pathogenesis of ALI with microcirculatory disturbance.MethodsWe conducted a single-center retrospective study for ALI and blood samples and liver tissues were analyzed to evaluate the microcirculatory disturbance in ALI patients (n = 120). Single-cell RNA sequencing analysis (scRNA-seq) was applied to the liver from the concanavalin A (Con A)‑induced mouse model of ALI. Interferon-gamma (IFNγ) and tumor necrosis factor-alpha knockout mice, and primary human liver sinusoidal endothelial cells (LSECs) were used to assess the mechanism of microcirculatory disturbance.ResultsThe serum IFNγ concentrations were significantly higher in ALI patients with microcirculatory disturbance than in patients without microcirculatory disturbance, and the IFNγ was upregulated in the Con A mouse model which presented microcirculatory disturbance. Hepatic IFNγ expression was increased as early as 1 hour after Con A treatment prior to sinusoidal hypercoagulation and hypoxic liver damage. scRNA-seq revealed that IFNγ was upregulated in innate lymphoid cells and stimulated hepatic vascular endothelial cells at the early stage of liver injury. In IFNγ knockout mice treated with Con A, the sinusoidal hypercoagulation and liver damage were remarkably attenuated, concomitant with the complete inhibition of CD40 and tissue factor (TF) upregulation in vascular endothelial cells. By ligand-receptor analysis, CD40-CD40 ligand interaction was identified in vascular endothelial cells. In human LSECs, IFNγ upregulated CD40 expression and TF was further induced by increased CD40-CD40 ligand interaction. Consistent with these findings, hepatic CD40 expression was significantly elevated in human ALI patients with microcirculatory disturbance.ConclusionWe identified the critical role of the IFNγ-CD40 axis as the molecular mechanism of microcirculatory disturbance in ALI. This finding may provide novel insights into the pathogenesis of ALI and potentially contribute to the emergence of new therapeutic strategies for ALI patients.

Efficacy and Safety of Alprostadil in Microcirculatory Disturbances During Emergency PCI: A Meta-Analysis of Randomized Controlled Trials.

The clinical advantage of alprostadil [prostaglandin E1 (PGE1)] in the treatment of microcirculatory disturbances (defined as no-reflow or slow-flow) in acute percutaneous coronary intervention (PCI) is still disputed. The purpose of our study was to review the efficacy of PGE1 supplements in patients with acute myocardial infarction (AMI) who had urgent PCI. This study was a meta-analysis of randomized controlled trials. PubMed, Embase, the Cochrane Library, Ovid, ProQuest, Scopus, the Chinese BioMedical Literature Database, China National Knowledge Internet, the China Science and Technology Journal Database, and the Wanfang Data Knowledge Service Platform were used as sources. We included randomized controlled trials including PGE1 for the treatment of intraoperative microcirculatory disorders and major cardiovascular adverse events in emergency PCI in people with AMI. Independent data extraction was conducted, and study quality was assessed. The meta-analysis was carried out by using random effects models to calculate the risk ratio (RR) of microcirculatory disorders between groups receiving PGE1 and those receiving placebo, nitroglycerin, or tirofiban. The primary endpoint of the study was the incidence of microcirculatory disturbances. Secondary outcomes included corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC), the percentage of patients with TIMI myocardial perfusion grade 3 (TMPG3), and the percentage of patients with myocardial blush grade 3 (MBG3) as efficacy indicators. Additionally, major adverse cardiovascular events (MACE) at 30 days and 180 days were assessed as safety indicators. There were 18 trials involving a total of 1458 participants. PGE1 significantly reduced the occurrence of microcirculation disorders compared with conventional medications and placebo [risk ratio 0.48, 95% confidence interval (CI) 0.36-0.63, I2 = 46%; cTFC (RR -4.74, 95% -6.85 to -2.63, I2 93%); percentage of patients with TMPG3 (RR 1.34, 95% CI 1.07-1.68, I2 70%) or MBG3 (RR 1.33, 95% CI 1.19-1.49, I2 0%); major adverse cardiovascular events (MACEs) in 30 days (RR 0.48, 95% CI 0.27-0.86, I2 0%); and MACEs in 180 days (RR 0.41, 95% CI 0.28-0.60, I2 0%)]. We found thatPGE1 decreased the occurrence of micro-circulation disturbance in AMI and enhanced the outcome of PCI.Additional studies should be conducted to confirm these findings.

Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis.

Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occur through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that is dependent on Angiopoietin (Ang-2) and vascular endothelial growth factor (VEGF). In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and post-mortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcome were analyzed in BM patients. Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human brain metastases negatively correlated with survival. Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevent the outgrowth of macrometastases.

A neural-mast cell axis regulates skin microcirculation in diabetes.

Changes in microcirculation lead to the progression of organ pathology in diabetes. Although neuroimmune interactions contribute to a variety of conditions, it is still unclear whether abnormal neural activities affect microcirculation related to diabetes. Using laser speckle contrast imaging, we examined the skin of patients with type 2 diabetes and found that their microvascular perfusion was significantly compromised. This phenomenon was recapitulated in a high-fat-diet-driven murine model of type 2 diabetes-like disease. In this setting, although both macrophages and mast cells were enriched in the skin, only mast cells and associated degranulation were critically required for the microvascular impairment. Sensory neurons exhibited enhanced TRPV1 activities, which triggered mast cells to degranulate and compromise skin microcirculation. Chemical and genetic ablation of TRPV1+ nociceptors robustly improve skin microcirculation status. Substance P (SP) is a neuropeptide and was elevated in the skin and sensory neurons in the context of type 2 diabetes. Exogenous administration of SP resulted in impaired skin microcirculation, whereas neuronal knockdown of SP dramatically prevented mast cell degranulation and consequently improved skin microcirculation. Overall, our findings indicate a neural-mast cell axis underlying skin microcirculation disturbance in diabetes and shed light on neuroimmune therapeutics for diabetes-related complications.

An-Gong-Niu-Huang-Wan (AGNHW) regulates cerebral blood flow by improving hypoperfusion, cerebrovascular reactivity and microcirculation disturbances after stroke

BackgroundThe restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke. An-Gong-Niu-Huang-Wan (AGNHW) is a famous traditional compound Chinese medicine that has been used for over 220 years to treat acute ischaemic stroke; however, its role in the regulation of cerebral blood flow is still unclear. The aim of the present study was to investigate the regulatory effect of AGNHW on cerebral blood flow and microcirculation after ischaemic stroke and to elucidate the underlying mechanisms involved.MethodsMale C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO) and randomly assigned to the sham, MCAO, or AGNHW groups. AGNHW was administered intragastrically 1 h after dMCAO. The rotarod test was utilized to evaluate behavioural function; TTC was used to determine the infarct volume; and ischaemic injury was assessed by detecting brain levels of SOD, MDA and NO. Then, cortical perfusion and acetazolamide-induced cerebrovascular reactivity were assessed using laser speckle contrast imaging, and the velocity and flux of red blood cells in cortical capillaries were detected using two-photon laser scanning microscopy. In addition, we employed RNA-Seq to identify variations in gene expression profiles and assessed endothelium-dependent changes in microcirculatory dysfunction by measuring vasoactive mediator levels.ResultsAGNHW significantly increased cerebral blood flow, reduced the infarct volume, and promoted functional recovery after cerebral ischaemia. AGNHW increased the velocity and flux of red blood cells in capillaries and improved cerebrovascular reactivity in the ischaemic cortex. Furthermore, AGNHW regulated endothelium-dependent microcirculation, as evidenced by decreases in the expression of endothelins (Edn1, Edn3 and Ednrb) and the ratios of brain and serum TXB2/6-keto-PGF1α and ET-1/CGRP.ConclusionsAGNHW improved cerebral hypoperfusion, regulated cerebrovascular reactivity and attenuated microcirculatory dysfunction within the ischaemic cortex after stroke. This outstanding effect was achieved by modulating the expression of genes related to vascular endothelial cell function and regulating endothelium-dependent vasoactive mediators.