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Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wild-type mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: Previous research on diagnostic assessment by superb microvascular imaging (SMI) were based on qualitative or semi-quantitative assessments of vascularity, which may be subjective and unrepeatable by different sonographers. This study aimed to evaluate diagnostic performance of SMI Image-pro Plus (IPP) based vascular index (VI) for malignant renal masses., Method: We retrospectively reviewed 222 masses in 214 patients who underwent SMI between August 2019 and August 2022 in our study. We evaluated the diagnostic performance of blood flow via Alder grade, VI based on both IPP and SMI., Results: The kappa consistency of the Adler grade and VI for renal masses was classified among different observers were 0.765 and 0.824. The intra-observers correlation ecoefficiency (ICC) were 0.727 and 0.874. Benign renal masses were mainly Adler grade 0, grade I, and grade II, VI was 4.30 ± 4.27 (Range 0.98-16.42); while malignant masses were mainly Adler grade III, VI was 14.95 ± 10.94 (Range 0.79-56.89). VI was higher in malignant than benign masses (t = 15.638, P < 0.01). Among the malignant masses, the mean VI in clear cell renal cell carcinoma was higher than that in papillary renal cell carcinoma and chromophobe renal cell carcinoma (F = 30.659, P < 0.01). The sensitivity, specificity and accuracy of SMI were 80.00%, 71.15%, and 78.64%, respectively. The sensitivity, specificity, and accuracy were 60.59%, 88.46%, and 80.18% by using a VI of 7.95 as the cutoff value to identify malignant lesions from benign masses yielded. VI had better diagnostic efficiency than ultrasonic characteristics and Adler grade in benign and malignant differential diagnosis (Z = 4.851, P < 0.01; Z = 2.732, P < 0.01)., Conclusion: VI was higher in malignant than benign in renal masses. In malignant masses, VI in CCRCC was higher than that in papillary renal cell carcinoma and ChRCC. As a noninvasive examination, it had important clinical significance in the differential diagnosis of renal masses. VI from IPP may assist sonographer in distinguish renal malignances as a quantitative tool for vascularity., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Biopsy-based transcript diagnostics may identify molecular antibody-mediated rejection (AMR) when microvascular inflammation (MVI) is absent. In this single-center cohort, biopsy-based transcript diagnostics were validated in 326 kidney allograft biopsies. A total of 71 histological AMR and 35 T cell-mediated rejection (TCMR) cases were identified as molecular AMR and TCMR in 55% and 63%, respectively. Among 121 cases without MVI (glomerulitis + peritubular capillaritis = 0), 45 (37%) donor-specific antibody (DSA)-positive and 76 (63%) DSA-negative cases were analyzed. Twenty-one out of the 121 (17%) cases showed borderline changes, or TCMR, while BK nephropathy was excluded. None of the 45 DSA-positive patients showed molecular AMR. Among 76 DSA-negative patients, 2 had mixed molecular AMR/TCMR. All-AMR phenotype scores (sum of R4-R6) exhibited median values of 0.13 and 0.12 for DSA-positive and DSA-negative patients, respectively (P = .84). A total of 13% (6/45) DSA-positive and 11% (8/76) DSA-negative patients showed an all-AMR phenotype score > 0.30 (P = .77). Patients with a higher all-AMR phenotype score showed 33% more histologic TCMR (P = .005). The median all-AMR phenotype scores of glomerular basement membrane double contours = 0 and glomerular basement membrane double contours > 0 biopsies were 0.12 and 0.10, respectively (P = .35). Biopsy-based transcript diagnostics did not identify molecular AMR in cases without MVI. Follow-up biopsies and outcome data should evaluate the clinical relevance of subthreshold molecular alterations., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose, as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Interactions between endothelial cells (ECs) and mural pericytes (PCs) are critical in maintaining the stability and function of the microvascular wall. Abnormal interactions between these two cell types are a hallmark of progressive fibrotic diseases such as systemic sclerosis (also known as scleroderma). However, the role of PCs in signaling microvascular dysfunction remains underexplored. We hypothesized that integrin-matrix interactions contribute to PC migration from the vascular wall and conversion into interstitial myofibroblasts. Herein, pro-inflammatory tumor necrosis factor α (TNFα) or a fibrotic growth factor [transforming growth factor β1 (TGF-β1)] were used to evaluate human PC inflammatory and fibrotic phenotypes by assessing their migration, matrix deposition, integrin expression, and subsequent effects on endothelial dysfunction. Both TNFα and TGF-β1 treatment altered integrin expression and matrix protein deposition, but only fibrotic TGF-β1 drove PC migration in an integrin-dependent manner. In addition, integrin-dependent PC migration was correlated to changes in EC angiopoietin-2 levels, a marker of vascular instability. Finally, there was evidence of changes in vascular stability corresponding to disease state in human systemic sclerosis skin. This work shows that TNFα and TGF-β1 induce changes in PC integrin expression and matrix deposition that facilitate migration and reduce vascular stability, providing evidence that microvascular destabilization can be an early indicator of tissue fibrosis., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Ferroptosis is a new form of cell death characterized by iron-dependent lipid peroxidation. Whether ferroptosis is involved in retinal microvascular dysfunction under diabetic condition is not known. Herein, the expression of ferroptosis-related genes in patients with proliferative diabetic retinopathy and in diabetic mice was determined with quantitative RT-PCR. Reactive oxygen species, iron content, lipid peroxidation products, and ferroptosis-associated proteins in the cultured human retinal microvascular endothelial cells (HRMECs) and in the retina of diabetic mice were examined. The association of ferroptosis with the functions of endothelial cells in vitro was evaluated. After administration of ferroptosis-specific inhibitor, Fer-1, the retinal microvasculature in diabetic mice was assessed. Characteristic changes of ferroptosis-associated markers, including glutathione peroxidase 4, ferritin heavy chain 1, long-chain acyl-CoA synthetase 4, transferrin receptor protein 1, and cyclooxygenase-2, were detected in the retinal fibrovascular membrane of patients with proliferative diabetic retinopathy, cultured HRMECs, and the retina of diabetic mice. Elevated levels of reactive oxygen species, lipid peroxidation, and iron content were found in the retina of diabetic mice and in cultured HRMECs. Ferroptosis was found to be associated with HRMEC dysfunction under high-glucose condition. Inhibition of ferroptosis with specific inhibitor Fer-1 in diabetic mice significantly reduced the severity of retinal microvasculopathy. Ferroptosis contributes to microvascular dysfunction in diabetic retinopathy, and inhibition of ferroptosis might be a promising strategy for the therapy of early-stage diabetic retinopathy., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The prognosis of HCC patients without MVI (so called M0) is highly heterogeneous and the need for adjuvant therapy is still controversial., Methods: Patients with HCC with M0 who underwent liver resection (LR) or liver transplantation (LT) as an initial therapy were included. The Eastern Hepatobiliary Surgery Hospital (EHBH)-M0 score was developed from a retrospective cohort to form the training cohort. The classification which was developed using multivariate cox regression analysis was externally validated., Results: The score was developed using the following factors: α-fetoprotein level, tumour diameter, liver cirrhosis, total bilirubin, albumin and aspartate aminotransferase. The score differentiated two groups of M0 patients (≤3, >3 points) with distinct long-term prognoses outcomes (median overall survival (OS), 98.0 vs. 46.0 months; p < 0.001). The predictive accuracy of the score was greater than the other commonly used staging systems for HCC. And for M0 patients with a higher score underwent LR. Adjuvant transcatheter arterial chemoembolization (TACE) was effective to prolong OS., Conclusions: The EHBH M0 scoring system was more accurate in predicting the prognosis of HCC patients with M0 after LR or LT. Adjuvant therapy is recommended for HCC patients who have a higher score., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hepatectomy is widely considered a potential treatment for hepatocellular carcinoma (HCC). Unfortunately, one-third of HCC patients have tumor recurrence within 2 years after surgery (early recurrence), accounting for more than 60% of all recurrence patients. Early recurrence is associated with a worse prognosis. Previous studies have shown that microvascular invasion (MVI) is one of the key factors for early recurrence and poor prognosis in patients with HCC after surgery. This paper reviews the latest literature and summarizes the predictors of MVI, the correlation between MVI and early recurrence, the identification of suspicious nodules or subclinical lesions, and the treatment strategies for MVI-positive HCC. The aim is to explore the management of patients with MVI-positive HCC., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3A V/F158 [rs396991], KLRC2 wt/del , KLRK1 HNK/LNK [rs1049174], rs9916629-C/T). Fifty patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2 wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] vs 0 [0-1] in KLRC2 wt/del recipients; P = .001) and remained significant in a proportional odds multivariable model (odds ratio, 7.84; 95% confidence interval, 2.37-30.47; P = .001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Microvascular invasion (MVI) has been clinically recognized as a prognostic factor for hepatocellular carcinoma (HCC) after surgical treatment. Detection of MVI before surgical operation greatly benefit patients' prognosis and survival. Most of the existing methods for automatic diagnosis of MVI directly use deep neural networks to make predictions, which do not take into account clinical knowledge and lack of interpretability. To simulate the radiologists' decision process, this paper proposes a Two-stage Expert-guided Diagnosis (TED) framework for MVI in HCC. Specifically, the first stage aims to predict key imaging attributes for MVI diagnosis, and the second stage leverages these predictions as a form of attention as well as soft supervision through a variant of triplet loss, to guide the fitting of the MVI diagnosis network. The attention and soft supervision are expected to jointly guide the network to learn more semantically correlated representations and thereafter increase the interpretability of the diagnosis network. Extensive experimental analysis on a private dataset of 466 cases has shown that the proposed method achieves 84.58% on AUC and 84.07% on recall, significantly exceeding the baseline methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Microvascular invasion (MVI) is a significant risk factor affecting survival outcomes of patients after R0 liver resection (LR) for hepatocellular carcinoma (HCC). The current classification of MVI is not refined enough to prognosticate long-term survival of these patients, and a new MVI classification is needed., Methods: Patients with HCC who underwent R0 LR at the Eastern Hepatobiliary Surgery Hospital from January 2013 to December 2013 and with resected specimens showing MVI were included in this study with an aim to establish a novel MVI classification. The classification which was developed using multivariate cox regression analysis was externally validated., Results: There were 180 patients in the derivation cohort and 131 patients in the external validation cohort. The following factors were used for scoring: α-fetoprotein level (AFP), liver cirrhosis, tumor number, tumor diameter, MVI number, and distance between MVI and HCC. Three classes of patients could be distinguished by using the total score: class A, ≤3 points; class B, 3.5-5 points and class C, >5 points with distinct long-term survival outcomes (median recurrence free survival (mRFS), 22.6, 10.2, and 1.9 months, P < 0.001). The predictive accuracy of this classification was more accurate than the other commonly used classifications for HCC patients with MVI. In addition, the mRFS of class C patients was significantly prolonged (1.9 months vs. 6.2 months, P < 0.001) after adjuvant transcatheter arterial chemoembolization (TACE)., Conclusions: A novel MVI classification was established in predicting prognosis of HCC patients with MVI after R0 LR. Adjuvant TACE was useful for class C patients., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Microvascular invasion (MVI) adversely affects long-term survival in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). This study aimed to examine the association between preoperative type 2 diabetes mellitus (T2DM) with incidences of MVI and prognosis in HBV-related HCC after liver resection (LR)., Material and Methods: Data of HBV-related HCC patients who underwent LR as an initial therapy from four hospitals in China were retrospectively collected. Clinicopathological factors associated with the incidence of MVI were identified using univariate and multivariate logistic regression analysis. The recurrence-free survival (RFS) and overall survival (OS) curves between different cohorts of patients were generated using the Kaplan-Meier method and compared using the log-rank test., Results: Of 1473 patients who were included, 219 (14.9%) patients had T2DM. Preoperative T2DM, HBV DNA load, antiviral treatment, AFP level, varices, and tumor encapsulation were identified to be independent predictors of the incidence of MVI. Patients with HBV-related HCC and T2DM had a higher incidence of MVI (65.8%) than those without T2DM (55.4%) (P = 0.004). The RFS and OS were significantly worse in patients with T2DM than those without T2DM (median RFS: 11.1 vs 16.7 months; OS: 26.4 vs 42.6 months, both P < 0.001). Equivalent results were obtained in HCC patients with MVI who had or did not have T2DM (median RFS: 10.0 vs 15.9 months; OS: 24.5 vs 37.9 months, both P < 0.001)., Conclusions: Preoperative T2DM was an independent risk factor of incidence of MVI. Patients with HBV-related HCC and T2DM had worse prognosis than those without T2DM after LR., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The vascular pathology of peripheral artery disease (PAD) encompasses abnormal microvascular architecture and fibrosis in response to ischemia-reperfusion (I/R) cycles. We aimed to investigate the mechanisms by which pathological changes in the microvasculature direct fibrosis in the context of I/R., Methods: Primary human aortic endothelial cells (ECs) were cultured under cycles of normoxia-hypoxia (NH) or normoxia-hypoxia-hyperoxia (NHH) to mimic I/R. Primary human aortic smooth muscle cells (SMCs) were cultured and treated with media from the ECs., Findings: The mRNA and protein expression of the pro-fibrotic factors platelet derived growth factor (PDGF)-BB and connective tissue growth factor (CTGF) were significantly upregulated in ECs undergoing NH or NHH cycles. Treatment of SMCs with media from ECs undergoing NH or NHH cycles led to significant increases in TGF-β1, TGF-β pathway signaling intermediates, and collagen expression. Addition of neutralizing antibodies against PDGF-BB and CTGF to the media blunted the increases in TGF-β1 and collagen expression. Treatment of SMCs with PAD patient-derived serum also led to increased TGF-β1 levels., Interpretation: In an in-vitro model of I/R, which recapitulates the pathophysiology of PAD, increased secretion of PDGF-BB and CTGF by ECs was shown to be predominantly driving TGF-β1-mediated expression by SMCs. These cell culture experiments help elucidate the mechanism and interaction between ECs and SMCs in microvascular fibrosis associated with I/R. Thus, targeting these pro-fibrotic factors may be an effective strategy to combat fibrosis in response to cycles of I/R., Funding: National Institute on Aging at the National Institutes of Health grant number R01AG064420., Research in Context: Evidence before this study: Previous studies in gastrocnemius biopsies from peripheral artery disease (PAD) patients showed that transforming growth factor beta 1 (TGF-β1), the most potent inducer of pathological fibrosis, is increased in the vasculature of PAD patients and correlated with collagen deposition. However, the exact cellular source of TGF-β1 remained unclear. Added value of this study: Exposing cells to cycles of normoxia-hypoxia-hyperoxia (NHH) resulted in pathological changes that are consistent with human PAD. This supports the idea that the use of NHH may be a reliable, novel in vitro model of PAD useful for studying associated pathophysiological mechanisms. Furthermore, pro-fibrotic factors (PDGF-BB and CTGF) released from endothelial cells were shown to induce a fibrotic phenotype in smooth muscle cells. This suggests a potential interaction between these cell types in the microvasculature that drives increased TGF-β1 expression and collagen deposition. Thus, targeting these pro-fibrotic factors may be an effective strategy to combat fibrosis in response to cycles of ischemia-reperfusion., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Many long non-coding RNAs (lncRNAs) have been suggested to play critical roles in the pathogenesis of ischemic stroke, including lncRNA rhabdomyosarcoma 2-associated transcript (RMST). We aimed to elucidate the role and molecular mechanism of RMST in ischemic stroke., Materials and Methods: The in vitro ischemic stroke model was established by treating brain microvascular endothelial cells with oxygen-glucose deprivation (OGD). The expression of RMST, miR-204-5p and vascular cell adhesion molecule 1 (VCAM1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between miR-204-5p and RMST or VCAM1 was confirmed using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Cell viability, migration and apoptosis were assessed by Cell Counting Kit-8 (CCK-8), wound healing assay and flow cytometry, respectively. Lactic dehydrogenase (LDH) leakage rate was determined by LDH activity assay kit. The protein level of VCAM1 was analyzed by western blot (WB) assay., Key Findings: RMST was upregulated in OGD-treated HBMEC and bEnd.3 cells. MiR-204-5p was a direct target of RMST, and miR-204-5p inhibition abated the inhibitory effect of RMST knockdown on OGD-induced injury via inhibiting cell viability and migration and promoting apoptosis in HBMEC and bEnd.3 cells. Moreover, VCAM1 was identified as a direct target of miR-204-5p, and VCAM1 alleviated the effect of miR-204-5p on reduction of OGD-induced injury in HBMEC and bEnd.3 cells. In addition, RMST regulated VCAM1 expression via sponging miR-204-5p., Significance: RMST knockdown attenuated OGD-induced injury of HBMEC and bEnd.3 cells via regulating miR-204-5p/VCAM1 axis, indicating a possible therapeutic strategy for future ischemic stroke therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Heart disease and vascular disease positively correlate with the incidence of Alzheimer's disease (AD). Although there is ostensible involvement of dysfunctional cerebrovasculature in AD pathophysiology, the characterization of the specific changes and development of vascular injury during AD remains unclear. In the present study, we established a time-course for the structural changes and degeneration of the angioarchitecture in AD. We used cerebrovascular corrosion cast and µCT imaging to evaluate the geometry, topology, and complexity of the angioarchitecture in the brain of wild type and 3xTg AD mice. We hypothesized that changes to the microvasculature occur early during the disease, and these early identifiable aberrations would be more prominent in the brain subregions implicated in the cognitive decline of AD. Whole-brain analysis of the angioarchitecture indicated early morphological abnormalities and degeneration of microvascular networks in 3xTg AD mice. Our analysis of the hippocampus and cortical subregions revealed microvascular degeneration with onset and progression that was subregion dependent., (Copyright © 2021. Published by Elsevier Inc.)

Background: Apolipoprotein M (ApoM) may have a role in the susceptibility of type 2 diabetes mellitus (T2DM). Polymorphisms in the promoter region of the ApoM gene were found to be significantly associated with diabetes. The aim of this study was to investigate the association of ApoM SNP rs805297 (C-1065A) with the susceptibility of T2DM and related microvascular complications in South Egypt., Methods: We conducted a case-control study of 60 T2DM patients and 60 healthy control subjects. Lipid profile, fasting, and 2 hours postprandial glucose and creatinine levels were estimated. Patients were subjected to general and Fundus examinations, and screening for nephropathy by urinary albumin levels. ApoM level was assayed by ELISA. Genotyping of the human ApoM gene polymorphism SNP rs805297 (C-1065A) was done by PCR-restriction fragment length polymorphism followed by sequencing to confirm the polymorphism results., Results: ApoM was not different between T2DM and the control group (p=0.075) and was negatively correlated with LDL-c (p=0.029). There were significant differences in ApoM genotypes (p=0.001) and allele frequencies (p=0.019) between T2DM and the control group. A significant reduction in FBG, 2hPPG, and HbA1c levels in the heterozygous than the wild genotype in the group with diabetes with no difference in other lab parameters and microvascular complications. The C-allele is associated with lower blood glucose levels and retinopathy. The wild (CC) genotype is considered as a risk factor for developing T2DM in South Egyptians but not CA+AA genotypes., Conclusions: In South Egyptians the ApoM polymorphism rs805297 (C-1065A) wild type (CC) was associated with T2DM susceptibility and may have a role in controlling hyperglycemia in these patients. The A-allele is associated with hyperglycemia and diabetic retinopathy., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objective: Reperfusion therapy is a standard therapeutic strategy for acute stroke. Non-favorable outcomes are thought to partially result from impaired microcirculatory flow in ischemic tissue. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in stroke. One suggested therapeutic mechanism is the restoration of the microvasculature. The goal of this study was to determine whether infused MSCs enhance the therapeutic efficacy of reperfusion therapy following stroke in rats., Methods: First, to establish a transient middle cerebral artery occlusion (MCAO) model displaying approximately identical neurologic function and lesion volume as seen in permanent MCAO (pMCAO) at day 7 after stroke induction, we transiently occluded the MCA for 90, 110, and 120 minutes. We found that the 110-minute occlusion met these criteria and was used as the transient MCAO (tMCAO) model. Next, 4 MCAO groups were used to compare the therapeutic efficacy of infused MSCs: (1) pMCAO+vehicle, (2) tMCAO+vehicle, (3) pMCAO+MSC, and (4) tMCAO+MSC. Our ischemic model was a unique ischemic model system in which both pMCAO and tMCAO provided similar outcomes during the study period in the groups without MSC infusion groups. Behavioral performance, ischemic volume, and regional cerebral blood flow (rCBF) using arterial spin labeling-magnetic resonance imaging and histologic evaluation of microvasculature was performed., Results: The behavioral function, rCBF, and restoration of microvasculature were greater in group 4 than in group 3. Thus, infused MSCs facilitated the therapeutic efficacy of MCA reperfusion in this rat model system., Conclusions: Intravenous infusion of MSCs may enhance therapeutic efficacy of reperfusion therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pericytes (PC) are microvascular mural cells that make specific cell-to-cell contacts with the endothelial cells (EC). These cells are obligatory constituents of the microvessels including the retinal vasculature and they serve as regulators of vascular development, stabilization, maturation and remodeling. During early stages of diabetic retinopathy (DR), apoptotic loss of PC surrounding the retinal vasculature occurs. This may lead to reduced vessel stability, the onset of EC apoptosis, and subsequent retinal ischemia leading to angiogenesis and eventually, severe vision loss due to late proliferative diabetic retinopathy (PDR). Similarly, diabetic nephropathy (DN) is a chronic kidney disease due to hyperglycemia that particularly affects renal PC. Chronic high blood glucose level causes migration of peritubular PC away from the capillary into the interstitial space, which destabilizes the micro vessels, resulting in microvascular rarefaction. In both diabetes associated complications, the identification of specific biomarkers is necessary to stabilize the PC at an early stage. This review largely covers the importance of PC towards the pathogenesis of diabetes associated complications, and their heterogeneity in healthy and angiogenic vasculature., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Thrombotic, vascular, and bleeding complications are the most common causes of morbidity and mortality in the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In these disorders, circulating red cells, leukocytes, and platelets, as well as some vascular endothelial cells, each have abnormalities that are cell-intrinsic to the MPN driver mutations they harbor (eg, JAK2 V617F). When these cells are activated in the MPNs, their interactions with each other create a highly proadhesive and prothrombotic milieu in the circulation that predisposes patients with MPN to venous, arterial, and microvascular thrombosis and occlusive disease. Bleeding problems in the MPNs are caused by the MPN blood cell-initiated development of acquired von Willebrand disease. The inflammatory state created by MPN stem cells in their microenvironment extends systemically to amplify the clinical thrombotic tendency and, at the same time, preferentially promote further MPN stem cell clonal expansion, thereby generating a vicious cycle that favors a prothrombotic state in these diseases., (© 2021 by The American Society of Hematology.)

We concisely review clinical, autopsy, experimental and molecular data of 2019 coronavirus disease (COVID-19). Angiotensin-converting enzyme 2 disruption and thromboinflammatory microangiopathy emerge as distinctive features. Briefly, entry of the virus into microvessels can profoundly disrupt the local renin-angiotensin system, cause endothelial injury, activate the complement cascade and induce powerful thromboinflammatory reactions, involving, in particular, von Willebrand factor, that, if widespread, may lead to microvascular plugging, ischemia and, ultimately, organ failure. We believe the current COVID-19 data consolidate a widely unrecognised paradigm of potentially fatal thromboinflammatory microvascular disease., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A significant amount of clinical and research interest in thrombosis is focused on large vessels (eg, stroke, myocardial infarction, deep venous thrombosis, etc.); however, thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Further, microvascular thrombosis has recently been demonstrated in patients with COVID-19, and has been proposed to mediate the pathogenesis of organ injury in this disease. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation. In this review, we discuss endogenous regulatory mechanisms that prevent thrombosis in the microcirculation, experimental approaches to induce microvascular thrombi, and clinical conditions associated with microvascular thrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation is anticipated to provide optimal therapeutic targets for patients with diseases accompanied by microvascular thrombosis., (Published by Elsevier Inc.)

Bothrops (lance-head pit vipers) venoms are rich in weaponised metalloprotease enzymes (SVMP). These toxic enzymes are structurally diverse and functionally versatile. Potent coagulotoxicity is particularly important for prey capture (via stroke-induction) and relevant to human clinical cases (due to consumption of clotting factors including the critical depletion of fibrinogen). In this study, three distinct isoforms of P-III class SVMPs (IC, IIB and IIC), isolated from Bothrops neuwiedi venom, were evaluated for their differential capacities to affect hemostasis of prey and human plasma. Furthermore, we tested the relative antivenom neutralisation of effects upon human plasma. The toxic enzymes displayed differential procoagulant potency between plasma types, and clinically relevant antivenom efficacy variations were observed. Of particular importance was the confirmation the antivenom performed better against prothrombin activating toxins than Factor X activating toxins, which is likely due to the greater prevalence of the former in the immunising venoms used for antivenom production. This is clinically relevant as the enzymes displayed differential potency in this regard, with one (IC) in particular being extremely potent in activating Factor X and thus was correspondingly poorly neutralised. This study broadens the current understanding about the adaptive role of the SVMPs, as well as highlights how the functional diversity of SVMP isoforms can influence clinical outcomes. Key Contribution: Our findings shed light upon the hemorrhagic and coagulotoxic effects of three SVMPs of the P-III class, as well as the coagulotoxic effects of SVMPs on human, avian and amphibian plasmas. Antivenom neutralised prothrombin-activating isoforms better than Factor X activating isoforms., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background Aims: Peripheral arterial disease (PAD) is a progressive, disabling ailment for which no effective treatment exists. Gene therapy-mediated neovascularization has emerged as a potentially useful strategy. We tested the angiogenic and arteriogenic efficacy and safety of a baculovirus (BV) encoding mutant, oxygen-resistant hypoxia-inducible factor 1-alpha (mHIF-1α), in rabbits with PAD., Methods: After assessing the transfection efficiency of the BV.mHIF-1α vector and its tubulogenesis potential in vitro, we randomized rabbits with experimental PAD to receive 1 × 10 9 copies of BV.mHIF-1α or BV.null (n = 6 per group) 7 days after surgery. Two weeks post-treatment, collateralization (digital angiography) and capillary and arteriolar densities (immunohistochemistry) were measured in the posterior limbs. Ischemic damage was evaluated in adductor and gastrocnemius muscle samples. Tracking of viral DNA in injected zones and remote tissues at different time points was performed in additional rabbits using a BV encoding GFP., Results: Angiographically visible collaterals were more numerous in BV.mHIF-1α-treated rabbits (8.12 ± 0.42 vs 6.13 ± 1.15 collaterals/cm 2 , P < 0.05). The same occurred with arteriolar (27.9 ± 7.0 vs 15.3 ± 4.0 arterioles/mm 2 ) and capillary (341.8 ± 109.9 vs 208.8 ± 87.7 capillaries/mm 2 , P < 0.05) densities. BV.mHIF-1α-treated rabbits displayed less ischemic muscle damage than BV.null-treated animals. Viral DNA and GFP mRNA were detectable only at 3 and 7 days after injection in hind limbs. Neither the virus nor GFP mRNA was detected in remote tissues., Conclusions: In rabbits with PAD, BV.mHIF-1α induced neovascularization and reduced ischemic damage, exhibiting a good safety profile at 14 days post-treatment. Complementary studies to evaluate its potential usefulness in the clinic are needed., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Aims: The dysregulation of circular RNAs (circRNAs) has been implicated in the progression of diabetic retinopathy (DR). This study aims to explore the role and underlying mechanism of hsa&#95;circ&#95;0081108 (circCOL1A2) in DR., Materials and Methods: circCOL1A2, vascular endothelial growth factor (VEGF) and miR-29b expression levels in human retinal microvascular endothelial cells (hRMECs) were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting. The biological functions of hRMECs were evaluated by MTT, transwell, tube formation, and vascular permeability assays, respectively. The interaction between miR-29b and circCOL1A2/VEGF was determined by dual luciferase assay. The release of VEGF was examined by ELISA. The in vivo role of circCOL1A2 was further verified in streptozotocin (STZ)-induced DR in mice. The pathological changes and VEGF expression in retinal tissues were detected by hematoxylin and eosin (HE) and immunohistochemical staining., Key Findings: High glucose (HG) challenge led to increased circCOL1A2, VEGF, MMP-2, MMP-9 levels, but decreased miR-29b level in hRMECs. In addition, circCOL1A2 sponged miR-29b to promote VEGF expression. Silencing of circCOL1A2 inhibited HG-induced proliferation, migration, angiogenesis and vascular permeability of hRMECs via enhancing miR-29b expression. Moreover, circCOL1A2/miR-29b axis participated in HG-induced increase in angiogenesis-related protein expression. Finally, circCOL1A2 knockdown suppressed angiogenesis via regulating miR-29b/VEGF axis in DR mice., Significance: circCOL1A2 facilities angiogenesis during the pathological progression of DR via regulating miR-29b/VEGF axis, suggesting that targeting circCOL1A2 may be a potential treatment for DR., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Pathological alterations in the brain can cause microglial activation (MA). Thus, inhibiting MA could provide a new approach for treating neurodegenerative disorders., Main Methods: To investigate the effect of C16 peptide and angiopoietin-1 (Ang1) on inflammation following MA, we stimulated microglial BV-2 cells with lipopolysaccharide (LPS) and used dexmedetomidine (DEX) as a positive control. Specific inhibitors of Tie2, αvβ3 and α5β1 integrins, and PI3K/Akt were applied to investigate the neuron-protective and anti-inflammatory effects and signaling pathway of C16 + Ang1 treatment in the LPS-induced BV-2 cells., Key Findings: Our results showed that C16 + Ang1 treatment reduced the microglia M1 phenotype but promoted the microglia M2 phenotype. In addition, C16 + Ang1 treatment suppressed leukocyte migration across human pulmonary microvascular endothelial cells, reduced the levels of pro-inflammatory factors [inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, tumor necrosis factor (TNF-α)], and cellular apoptosis factors (caspase-3 and p53), and decreased lactate dehydrogenase (LDH) release, but promoted anti-inflammatory cytokine (IL-10) expression and cell proliferation in the LPS-activated BV-2 cells. The signaling pathways underlying the neuron-protective and anti-inflammatory effects of C16 + Ang1 may be mediated by Tie2-PI3K/Akt, Tie2-integrin and integrin-PI3K/Akt., Significance: The neuron-protective and anti-inflammatory effects of C16 + Ang1 treatment included M1 to M2 microglia phenotype switching, blocking leukocyte transmigration, decreasing apoptotic and inflammatory factors, and promoting cellular viability., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To date, the surgical delay of skin flaps is the most common and reliable method that increases skin flap survival. In this study, we aimed to increase skin flap viability using preconditioning by microneedling. Seventy-two Sprague Dawley rats were randomly divided into control, surgical flap delay (SFD), and four microneedling groups (7 or 14 days of preconditioning with 0.5 mm or 1 mm needles). Modified McFarlane flaps were raised on the back of rats. In Group I, a caudal pedicled skin flap was raised and the flap survival rate was assessed on postoperative day 14. In the SFD group, a bipedicled flap was created and after 14 days of surgical delay, all skin flaps were raised. In the microneedling groups, 0.5 mm or 1 mm needles were used for 7 or 14 days. The flap survival rates of all microneedling and SFD groups were significantly higher than the control group. The plasma levels of vascular endothelial growth factor (VEGF) did not significantly differ between groups, but the VEGF level of skin samples in the SFD group was higher than the control group. The vessel counts of all microneedling and SFD groups were statistically higher than the control group in all skin samples taken before raising the flaps, but skin samples taken 14 days after raising the skin flap did not show any difference between groups. We showed that preconditioning by microneedling can be used to improve the viability of critical ischemic skin flaps at a level similar to surgical delay., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: Sepsis-induced acute respiratory distress syndrome (ARDS) is a common, high mortality complication in intensive care unit (ICU) patients. MicroRNA-92a (miR-92a) plays a role in many diseases, but its association with sepsis-induced ARDS is unclear., Materials and Methods: We enrolled 53 patients, including 17 with sepsis only, and 36 with sepsis-induced ARDS. Lipopolysaccharide (LPS) was used to stimulate pulmonary microvascular endothelial cells (HPMEC) and alveolar epithelial A549 cells, which were used to investigate the miR-92a roles in ARDS. MiR-92a expression levels in patient serum and cells were quantified using quantitative reverse transcription-polymerase chain reaction (RT-PCR), and protein expression was examined using Western blotting. The effect of miR-92a on apoptosis was examined using flow cytometry. Wound healing and transwell migration assays were used to evaluate cell migration., Key Findings: Serum miR-92a expression was higher in patients with sepsis-induced ARDS, when compared to patients with sepsis only. After LPS treatment in cells, miR-92a expression was higher when compared with control group, cell apoptosis and inflammatory responses were increased and cell migration was inhibited. However, cell apoptosis and inflammatory responses were decreased and cell migration was enhanced after miR-92a downregulation, when compared with inhibitor negative control (NC) group. Moreover, phosphorylated-Akt and phosphorylated-mTOR expression were increased after miR-92a inhibition., Significance: Our study provides evidence that circulating serum miR-92a could act as a risk factor for sepsis-induced ARDS. MiR-92a inhibition attenuated the adverse effects of LPS on ARDS through the Akt/mTOR signaling pathway., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Since microRNAs (miRNAs) represent as effective therapeutic targets for diabetic retinopathy (DR), we identified aberrantly expressed miRNAs related to cellular dysfunction in DR and further detected their potential targets. This study aimed to explore the synergistic effect of miR-216a, inducible nitric oxide synthase 2 (NOS2) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway on human retinal microvascular endothelial cell (HRMEC) injury in DR., Methods: The differentially expressed genes in DR were obtained by GEO database, and the downstream signaling pathways and upstream targeted miRNAs were obtained through bioinformatics analysis. Subsequently, a DR model rat was established, and the target miR-216a was overexpressed to observe the pathological and morphological changes of the rat retina and the levels of inflammatory factors. Then, HRMECs were extracted and added with d-Glucose, and then transfected with miR-216a, NOS2 or adding JAK/STAT signaling pathway specific inhibitor to observe changes in cell activity and inflammatory damage., Results: NOS2 was significantly upregulated, and the JAK/STAT signaling pathway was significantly activated in DR. miR-216a targeted NOS2, which played a protective role in the retina of DR rats. Moreover, in cell experiments, overexpression of miR-216a promoted the viability of HRMECs under d-glucose treatment, and inhibited NOS2 expression and the JAK/STAT signaling pathway activation., Conclusion: This study suggests that miR-216a protects against HRMECs injury in DR by suppressing the NOS2/JAK/STAT axis., Competing Interests: Declaration of Competing Interest All authors declare that there is no conflict of interests in this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Microvascular proliferation in glioblastoma multiforme is a biological key mechanism to facilitate tumor growth and infiltration and a main target for treatment interventions. The vascular architecture can be obtained by Single Plane Illumination Microscopy (SPIM) to evaluate vascular heterogeneity in tumorous tissue. We make use of the Gibbs point field model to quantify the order of regularity in capillary distributions found in the U87 glioblastoma model in a murine model and to compare tumorous and healthy brain tissue. A single model parameter Γ was assigned that is linked to tissue-specific vascular topology through Monte-Carlo simulations. Distributions of the model parameter Γ differ significantly between glioblastoma tissue with mean 〈Γ G 〉=2.1±0.4, as compared to healthy brain tissue with mean 〈Γ H 〉=4.9±0.4, suggesting that the average Γ-value allows for tissue differentiation. These results may be used for diagnostic magnetic resonance imaging, where it has been shown recently that Γ is linked to tissue-inherent relaxation parameters., (Copyright © 2020. Published by Elsevier Ltd.)

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Vaso-occlusive crisis (VOC) is the primary cause of morbidity and hospitalization in sickle cell disease (SCD); however, only 4 therapies (hydroxyurea, l-glutamine, crizanlizumab, and voxeletor) are currently approved in SCD. These agents limit the duration, severity, and frequency of crises. Activation of coagulation is a hallmark of SCD. Studies in animal models of SCD have shown that coagulation contributes to the chronic inflammation and end-organ damage associated with the disease; however, it is unknown whether coagulation directly contributes to the microvascular stasis that causes VOC. Herein, we demonstrate that inhibition of tissue factor (TF) and the downstream coagulation proteases factor Xa and thrombin significantly attenuates heme-induced microvascular stasis in mouse models of VOC. Pharmacologic inhibition of the principal thrombin receptor, protease activated receptor-1 (PAR-1), as well as deficiency of PAR-1 in all nonhematopoietic cells, also reduces stasis in sickle mice. PAR-1 deficiency was associated with reduced endothelial von Willebrand factor expression, which has been shown to mediate microvascular stasis. In addition, TF inhibition reduces lung vaso-occlusion in sickle mice mediated by arteriolar neutrophil-platelet microemboli. In sum, these results suggest that prophylactic anticoagulation might attenuate the incidence of VOC., (© 2020 by The American Society of Hematology.)

The disruption of the blood-spinal cord barrier (BSCB) following spinal cord injury contributes to inflammation and glial scarring that inhibits axon growth and diminishes the effectiveness of conduits transplanted to the injury site to promote this growth. The purpose of this study is to evaluate whether scaffolds containing microvessels that exhibit BSCB integrity reduce inflammation and scar formation at the injury site and lead to increased axon growth. For these studies, a self-assembling peptide scaffold, RADA-16I, is used due to its established permissiveness to axon growth and ability to support vascularization. Immunocytochemistry and permeability transport assays verify the formation of tight-junction containing microvessels within the scaffold. Peptide scaffolds seeded with different concentrations of microvascular cells are then injected into a spinal contusion injury in rats to evaluate how microvessels affect axon growth and neurovascular interaction. The effect of the vascularized scaffold on inflammation and scar formation is evaluated by quantifying histological sections stained with ED-1 and GFAP, respectively. Our results indicate that the peptide scaffolds containing microvessels reduce inflammation and glial scar formation and increase the density of axons growing into the injury/transplant site. These results demonstrate the potential benefit of scaffold vascularization to treat spinal cord injury. STATEMENT OF SIGNIFICANCE: This study evaluates the benefit of transplanting microvascular cells within a self-assembling peptide scaffold, RADA-16I, that has shown promise for facilitating regeneration in the central nervous system in previous studies. Our results indicate that vasculature featuring tight junctions that give rise to the blood-spinal cord barrier can be formed within the peptide scaffold both in vitro and in a rat model of a subacute contusion spinal cord injury. Histological analysis indicates that the presence of the microvessels encourages axon infiltration into the site of injury and reduces the area of astrocyte activation and inflammation. Overall, these results demonstrate the potential of vascularizing scaffolds for the repair of spinal cord injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Ltd.)

Ischemia due to hypoperfusion is one of the most common forms of acute kidney injury. We hypothesized that kidney hypoxia initiates the up-regulation of miR-218 expression in endothelial progenitor cells (EPCs) to guide endocapillary repair. Murine renal artery-derived EPCs (CD34 + /CD105 - ) showed down-regulation of mmu-Mir218-5p/U6 RNA ratio after ischemic injury, while in human renal arteries, MIR218-5p expression was up-regulated after ischemic injury. MIR218 expression was clarified in cell culture experiments in which increases in both SLIT3 and MIR218-2-5p expressions were observed after 5 minutes of hypoxia. ROBO1 transcript, a downstream target of MIR218-2-5p, showed inverse expression to MIR218-2-5p. EPCs transfected with a MIR218-5p inhibitor in three-dimensional normoxic culture showed premature capillary formation. Organized progenitor cell movement was reconstituted when cells were co-transfected with Dicer siRNA and low-dose Mir218-5p mimic. A Mir218-2 knockout was generated to assess the significance of miR-218-2 in a mammalian model. Mir218-2-5p expression was decreased in Mir218-2 -/- embryos at E16.5. Mir218-2 -/- decreased CD34 + angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2 +/- decreased peritubular capillary density at postnatal day 14 and increased serum creatinine after ischemia in adult mice. Systemic injection of miR-218-5p decreased serum creatinine after injury. These experiments demonstrate that miR-218 expression can be triggered by hypoxia and modulates EPC migration in the kidney., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In the setting of type-2 diabetes, there are declines of structural stability and functionality of blood capillaries and red blood cells (RBCs), increasing the risk for microcirculatory disturbances. Correcting hyperglycemia is not entirely effective at reestablishing normal cellular metabolism and function. Therefore, identification of pathological changes occurring before the development of overt hyperglycemia may lead to novel therapeutic targets for reducing the risk of microvascular dysfunction. Here we determine whether RBC-capillary interactions are altered by prediabetic hypersecretion of amylin, an amyloid forming hormone co-synthesized with insulin, and is reversed by endothelial cell-secreted epoxyeicosatrienoic acids. In patients, we found amylin deposition in RBCs in association with type-2 diabetes, heart failure, cancer and stroke. Amylin-coated RBCs have altered shape and reduced functional (non-glycated) hemoglobin. Amylin-coated RBCs administered intravenously in control rats upregulated erythropoietin and renal arginase expression and activity. We also found that diabetic rats expressing amyloid-forming human amylin in the pancreas (the HIP rat model) have increased tissue levels of hypoxia-inducible transcription factors, compared to diabetic rats that express non-amyloid forming rat amylin (the UCD rat model). Upregulation of erythropoietin correlated with lower hematocrit in the HIP model indicating pathologic erythropoiesis. In the HIP model, pharmacological upregulation of endogenous epoxyeicosatrienoic acids protected the renal microvasculature against amylin deposition and also reduced renal accumulation of HIFs. Thus, prediabetes induces dysregulation of amylin homeostasis and promotes amylin deposition in RBCs and the microvasculature altering RBC-capillary interaction leading to activation of hypoxia signaling pathways and pathologic erythropoiesis. Hence, dysregulation of amylin homeostasis could be a therapeutic target for ameliorating diabetic vascular complications., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

LncRNA small nucleolar RNA host gene 3 (Snhg3) has been involved in cell proliferation and migration in malignant cells. However, its role in regulating functions of non-malignant cells has been hardly reported. Here, we found Snhg3 expression was sharply induced in primary brain microvascular endothelial cells (BMVECs) treated with oxygen-and-glucose-deprivation (OGD) plus hemin, an in vitro model of intracerebral hemorrhage (ICH). Downregulation of Snhg3 by siRNA transfection improved cell proliferation and migration abilities and reduced cell apoptosis and monolayer permeability in BMVECs under treatment with OGD plus hemin. Snhg3 overexpression suppressed cell proliferation and migration and increased cell apoptosis and monolayer permeability under normal condition. In ICH rats, downregulation of Snhg3 by siRNA injection improved behavioral and histological manifestations, including number of right turns, limb placement score, integrity of blood-brain barrier (BBB), brain water content and cell apoptosis in vivo. In the mechanism exploration, we found that, TWEAK and Snhg3 displayed a positive correlation with each other. Snhg3 overexpression increased expression of TWEAK protein and its receptor Fn14, that were also induced by OGD plus hemin, activating the downstream neuroinflammatory pathway STAT3 and enhancing the secretion of MMP-2/9. Finally, the TWEAK-siRNA, the Fn14 inhibitor ATA and the STAT3 blocker AG490 were respectively used to treat BMVECs under treatment with OGD plus hemin. Our results showed either TWEAK downregulation, Fn14 inhibition, or STAT3 blockade, could rescue Snhg3-induced impairment of BMVEC functions. In conclusion, the lncRNA Snhg3 contributes to dysfunction of cerebral microvascular cells in ICH rats by activating the TWEAK/Fn14/STAT3 pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The benefits of adjuvant transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) remain controversial. We compared the efficacy and safety of adjuvant TACE and hepatic resection (HR) alone for HCC patients with MVI., Methods: The PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched to compare adjuvant TACE and HR alone for the treatment of HCC with MVI from inception to January 1, 2019. The study outcomes, including overall survival (OS) and disease-free survival (DFS), were extracted independently by two authors., Results: 12 trials involving 2190 patients were evaluated. A meta-analysis of 11 studies suggested that the 1-, 3-, and 5-year overall survival (OS) rates (OR = 0.33, P < 0.001; OR = 0.49, P < 0.001; and OR = 0.59, P < 0.01; respectively), favored adjuvant TACE over HR alone. 11 studies were included in the meta-analysis of DFS, and adjuvant TACE showed better 1-, 3-, and 5-DFS (OR = 0.45, P < 0.001; OR = 0.50, P < 0.001; and OR = 0.58, P < 0.001; respectively) compared to HR alone. Subgroup analysis demonstrated that adjuvant TACE could benefit HCC patients with MVI with tumor diameter >5 cm or multinodular tumors., Conclusion: Adjuvant TACE may improve OS and DFS for HCC patients with MVI compared to HR alone and should be recommended for selected HCC patients with MVI. However, these results need to be validated through further high-quality clinical studies., Lay Summary: The benefits of adjuvant TACE in HCC patients with microvascular invasion remain controversial. Twelve studies involving 2190 patients were include in our meta-analysis. Adjuvant TACE may improve OS and DFS for HCC patients with MVI compared to HR alone and should be recommended for selected HCC patients with MVI., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Cerebral microvascular occlusions cause restriction of blood supply to the brain, thus potentially severely impacting cognitive abilities. Thus, accurate prediction of thrombus growth in realistic geometries is important. Thrombi growth in an existing 13-generation cerebral microvasculature network is simulated here to study the haemodynamic effects of single and multiple blockages on the occlusion of the network. Compared to a single vessel, in a network, the occlusion probability is found to be different. It is the downstream/smaller arterioles (i.e. the 3rd, 4th, 5th, 6th generation arterioles in this study) that tend to reach occlusion first in a network and thus are the critical vessels. Simulations of simultaneous growth of two independent thrombi in the network (referred to here as the two-block case) show a close coupling between the locations of the various blocks in the network, each influencing the other's growth. The presence of the lead block (LB) slows the growth of the trailing block (TB). In some cases, it stops the TB's growth thereby preventing it from occluding the vessel. Findings in this work thus indicate that, to prevent ischaemia, blocks in the smaller arterioles need to be identified and treated first, and that this is more critical if the number of simultaneous blocks is higher., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Insular cortex (IC) ischemic strokes are associated with increased risk of cardiac arrhythmias. We have previously hypothesized that the anatomical substrate for post-stroke neurogenic arrhythmias comprises stroke-induced left atrium (LA) coronary microvascular endothelial dysfunction (CMED), and myocardial inflammatory infiltration (MII) leading to myocardial fibrosis. We investigated whether selectively induced IC ischemic stroke in rats results in histopathological changes in the LA., Methods: Insular ischemic stroke was induced in 6-month old male Wistar rats via unilateral stereotaxic injection of endothelin-1 into the left or right IC. The control group consisted of rats injected with saline. We histologically examined the LA 28 days after stroke for CMED, MII, and fibrosis. We performed linear regression analyses to assess correlation between the 3 histopathological outcomes. We compared these findings in the distal LA and the LA-pulmonary vein border (LA-PV border), a region of rich autonomic innervation., Results: Right and left IC stroke led to CMED, MII, and fibrosis in the LA. MII was significantly correlated with CMED and fibrosis. The LA-PV border had significantly greater MII and fibrosis than the distal LA. There were no differences in coronary microvascular and myocardial changes between left and right IC strokes., Conclusions: Left and right insular ischemic strokes resulted in CMED, MII, and fibrosis, the pathological hallmark of arrhythmogenic LA tissue. Since these changes were greater within the LA-PV border than in the distal LA tissue, the role of preganglionic fibers at the ganglionated plexi as part of neurogenic arrhythmogenesis warrants further investigation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor-specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long-term outcomes. We identified novel WNT pathway genes associated with microvascular injury and allograft failure in residual clinical biopsy specimens obtained up to 10 years earlier. Further mechanistic studies may identify the WNT pathway as a new diagnostic and therapeutic target., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Cerebrovascular pathology is common in aging and Alzheimer's disease (AD). The microvasculature is particularly vulnerable, with capillary-level microhemorrhages coinciding with amyloid beta deposits in senile plaques. In the current analysis, we assessed the relationship between cerebral microvessels and the neuritic component of the plaque in cortical and hippocampal 50- to 200-μm sections from 11 AD, 3 Down syndrome, and 7 nondemented cases in neuritic disease stages 0-VI. We report that 77%-97% of neuritic plaques are perivascular, independently of disease stage or dementia diagnosis. Within neuritic plaques, dystrophic hyperphosphorylated tau-positive neurites appear as clusters of punctate, bulbous, and thread-like structures focused around capillaries and colocalize with iron deposits characteristic of microhemorrhage. Microvessels within the neuritic plaque are narrowed by 1.0 ± 1.0 μm-4.4 ± 2.0 μm, a difference of 16%-65% compared to blood vessel segments with diameters 7.9 ± 2.0-6.4 ± 0.8 μm (p < 0.01) outside the plaque domain. The reduced capacity of microvessels within plaques, frequently below patency, likely compromises normal microlocal cerebrovascular perfusion. These data link the neuritic and amyloid beta components of the plaque directly to microvascular degeneration. Strategies focused on cerebrovascular antecedents to neuritic dystrophy in AD have immediate potential for prevention, detection, and therapeutic intervention., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: Although imaging techniques have demonstrated the existence of microvascular abnormalities in hypertrophic cardiomyopathy (HCM), a detailed histopathological assessment is lacking as well as a comparison between different phases of the disease. We aimed to compare microvasculopathy and myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) versus end-stage (ES) HCM., Methods: 27 myectomy specimens of HOCM patients and 30 ES-HCM explanted hearts were analyzed. Myocardial fibrosis was quantitatively determined with dedicated software and qualitatively classified as scar-like or interstitial. Intramural coronary arteries were evaluated separately according to lumen diameter: 100-500 μ versus <100 μ. Microvasculopathy assessment included the description of medial and intimal abnormalities and stenosis grading. The two subgroups were compared considering only the anterobasal septum of ES explanted hearts., Results: Median value of fibrosis in the anterobasal septum of explanted hearts was 34.6% as opposed to 10.3% of myectomy specimens (p < 0.001). Scar-like fibrosis was widely found in ES hearts while interstitial fibrosis was distinctive of HOCM (p < 0.001). All slides showed 100-500 μ microvasculopathy without any differences between subgroups in terms of lumen narrowing, extent of the disease and type of parietal involvement. Among ES hearts these lesions were associated with scar-like fibrosis (p = 0.034). <100-μ microvasculopathy was also frequent with no differences between subgroups., Conclusions: Microvasculopathy is an intrinsic feature of HCM with similar characteristics across the natural phases of the disease. Conversely, myocardial fibrosis changes over time with ES hearts showing a three-fold greater amount, mainly scar-like. ES showed a closer association between microvasculopathy and replacement fibrosis., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Fibrillary glomerulonephritis is a glomerular disease historically defined by glomerular deposition of Congo red-negative, randomly oriented straight fibrils that lack a hollow center and stain with antisera to immunoglobulins. It was initially considered to be an idiopathic disease, but recent studies highlighted association in some cases with autoimmune disease, malignant neoplasm, or hepatitis C viral infection. Prognosis is poor with nearly half of patients progressing to end-stage renal disease within 4 years. There is currently no effective therapy, aside from kidney transplantation, which is associated with disease recurrence in a third of cases. The diagnosis has been hampered by the lack of biomarkers for the disease and the necessity of electron microscopy for diagnosis, which is not widely available. Recently, through the use of laser microdissection-assisted liquid chromatography-tandem mass spectrometry, a novel biomarker of fibrillary glomerulonephritis, DnaJ homolog subfamily B member 9, has been identified. Immunohistochemical studies confirmed the high sensitivity and specificity of DnaJ homolog subfamily B member 9 for this disease; dual immunofluorescence showed its colocalization with IgG in glomeruli; and immunoelectron microscopy revealed its localization to individual fibrils of fibrillary glomerulonephritis. The identification of this tissue biomarker has already entered clinical practice and undoubtingly will improve the diagnosis of this rare disease, particularly in developing countries where electron microscopy is less available. Future research is needed to determine whether DnaJ homolog subfamily B member 9 is an autoantigen or just an associated protein in fibrillary glomerulonephritis, whether it can serve as a noninvasive biomarker, and whether therapies that target this protein are effective in improving prognosis., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the optic disc microvasculature in optic nerve head drusen (ONHD) vasculature in comparison to acute nonarteritic anterior ischemic optic neuropathy (NAION) and normal eyes using optical coherence tomography angiography (OCT-A)., Methods: Ten eyes with ONHD, 10 eyes with acute NAION, and 10 healthy eyes were included in this prospective, comparative, observational case series. OCT-A imaging was performed on the optic discs. Qualitative grading was performed for dilation and tortuosity of the peripapillary vessels by 3 graders. Quantitative comparison was performed for peripapillary and inside disc vessel densities in nerve head (NH) and retinal peripapillary capillary (RPC) slabs., Results: The intergrader agreement for dilation and tortuosity of the peripapillary vessels was poor (0.313 and 0.182 for vascular dilation in nerve head and radial peripapillary capillary enface images, respectively, and 0.478 and 0.490 for vascular tortuosity in nerve head and radial peripapillary capillary enface images, respectively). In NH en face images, the vessel density measurements were statistically significantly different between the 3 groups (all p < 0.05). In RPC en face images, the vessel density measurements were statistically significantly different between the 3 groups (all p < 0.05) except for nasal peripapillary sector (0.08)., Conclusion: Despite poor intergrader agreement in qualitative analysis, quantitative OCT-A evaluation may differentiate optic disc edema due to NAION from pseudodisc edema due to ONHD., (Copyright © 2018 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Ischemia-reperfusion injury (IRI) is the outcome of an inflammatory process that is triggered when an organ undergoes a transient reduction or cessation of blood flow, followed by re-establishment of perfusion. In the clinical setting, IRI contributes to significant acute kidney injury, patient morbidity and mortality, and adverse outcomes in transplantation. Tubular cell death by necrosis and apoptosis is a central feature of renal IRI. Recent research has challenged traditional views of cell death by identifying new pathways in which cells die in a regulated manner but with the morphologic features of necrosis. This regulated necrosis (RN) takes several forms, with necroptosis and ferroptosis being the best described. The precise mechanisms and relationships between the RN pathways in renal IRI are currently the subject of active research. The common endpoint of RN is cell membrane rupture, resulting in the release of cytosolic components with subsequent inflammation and activation of the immune system. We review the evidence and mechanisms of RN in the kidney following renal IRI, and discuss the use of small molecule inhibitors and genetically modified mice to better understand this process and guide potentially novel therapeutic interventions., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: This study assessed the prognostic value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in the prediction of MVI and early recurrence following resection., Method: This prospective study (ClinicalTrials.gov ID: NCT02145013) included 78 consecutive HCC patients who underwent 18F-FDG PET/CT before curative-intent resection from 2014 to 2017. Prognostic factors available before surgery for predicting MVI and early recurrence (≤2 years) were identified by univariate and multivariate analyses., Results: The 18F-FDG PET/CT result was positive in 30 (38%) patients. MVI was present in 33% (26/78) of specimens. Early recurrence occurred in 19% (14/74) of surviving patients. PET/CT positivity was the sole independent predictor of MVI (odds ratio [OR] = 3.6, 95% confidence interval [CI] = 1.1-11.2; p = 0.03), with a specificity and sensitivity for predicting MVI of 73% and 62%, respectively. Analysis of variables available before surgery showed that PET/CT positivity (hazard ratio [HR] = 5.8, 95% CI = 1.6-20.4; p = 0.006) and the male sex (HR = 6.6; 95% CI = 1.8-24.2; p = 0.005) were independent predictors of early recurrence., Conclusion: 18F-FDG PET/CT predicts MVI and early recurrence after surgery for HCC and could be used to select patients for neoadjuvant treatment., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The angioarchitecture of the spinal cord and microvascular changes after acute and subacute spinal cord injury (SCI) have been reported in rodents. Microvascular changes after chronic SCI have not been explored. We characterized three-dimensional microvascular changes during the chronic phase of cervical hemicontusion SCI in rats., Methods: At 12 weeks after 1.2-mm hemicontusion injury, microvascular parameters, including vascular volume, ratio of vascular volume to tissue volume, vascular number, and vascular separation, were measured at the epicenter and each cord segment, and the percentage and volume of spinal vessels with different diameters were measured by micro computed tomography at the injury segment., Results: The 1.2-mm hemicontusion injury applied a compressive force of 1.050 ± 0.103 N to the cord, resulting in a cavity and a significant decrease in microvasculature at the epicenter. The vascular volume, ratio of vascular volume to tissue volume, and vascular number of the C5 cord decreased by 40%, 38%, and 36% at 12 weeks after SCI, whereas vascular separation increased by 54% compared with the control group. In the chronic phase after SCI, the percentage and volume of spinal microvessels at the contusion segment decreased significantly (especially vessels with diameters <40 μm)., Conclusions: Blood supply to the cervical spinal cord is insufficient during the chronic phase of cervical hemicontusion SCI, especially in microvessels with diameters <40 μm. These results may provide a basis to explore microvascular changes of SCI during the chronic phase., (Copyright © 2019 Elsevier Inc. All rights reserved.)