Vascular Pathological Changes Research Articles

Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation

BackgroundLong-term survival after lung transplantation (LTx) remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types. MethodsPeripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, as well as epithelial and vascular abnormalities. ResultsCLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in pathological scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p=0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes and airway fibrosis. Immunofluorescence staining demonstrated a trend towards a lower frequency of club cells in CLAD, and a higher frequency of apoptotic club cells in BOS samples (p=0.01). ConclusionsCLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathological changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD pathological assessments.

Protective effect of vitexin against high fat-induced vascular endothelial inflammation through inhibiting trimethylamine N-oxide-mediated RNA m6A modification

A high-fat diet (HFD) is a major risk factor for cardiovascular disease.

HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress.

Phenotypic change of vascular smooth muscle cells (VSMCs) is the main contributor of vascular pathological remodeling in atherosclerosis. The endoplasmic reticulum (ER) is critical for maintaining VSMC function through elimination of misfolded proteins that impair VSMC cellular function. ER-associated degradation (ERAD) is an ER-mediated process that controls protein quality by clearing misfolded proteins. One of the critical regulators of ERAD is HRD1, which also plays a vital role in lipid metabolism. However, the function of HRD1 in VSMCs of atherosclerotic vessels remains poorly understood. The level of HRD1 expression was analyzed in aortic tissues of mice fed with a high-fat diet (HFD). The H&E and EVG (VERHOEFF'S VAN GIESON) staining were used to demonstrate pathological vascular changes. IF (immunofluorescence) and WB (western blot) were used to explore the signaling pathways in vivo and in vitro. The wound closure and transwell assays were also used to test the migration rate of VSMCs. CRISPR gene editing and transcriptomic analysis were applied in vitro to explore the cellular mechanism. Our data showed significant reduction of HRD1 in aortic tissues of mice under HFD feeding. VSMC phenotypic change and HRD1 downregulation were detected by cholesterol supplement. Transcriptomic and further analysis of HRD1-KO VSMCs showed that HRD1 deficiency induced the expression of genes related to ER stress response, proliferation and migration, but reduced the contractile-related genes in VSMCs. HRD1 deficiency also exacerbated the proliferation, migration and ROS production of VSMCs induced by cholesterol, which promoted the VSMC dedifferentiation. Our results showed that HRD1 played an essential role in the contractile homeostasis of VSMCs by negatively regulating ER stress response. Thus, HRD1 in VSMCs could serve as a potential therapeutic target in metabolic disorder-induced vascular remodeling.

Multicentric Hyaline-Vascular Castleman Disease: The Missing Link?

Introduction: Castleman disease (CD) is a rare lymphoproliferative disorder that encompasses distinct clinicopathological entities. Unicentric form of the disease (UCD) usually involves a single lymph node station, exhibits hyaline vascular (HV) pathological changes with follicular dendritic cell expansion, and may associate with specific and life-threatening complications including paraneoplastic pemphigus (PNP) and follicular dendritic cell sarcoma (FDCS). Plasma cell interfollicular infiltration is absent in the HV subtype as opposed to the Plasma-Cell (PC) or Mixed subtypes. PC subtype has been associated with inflammatory symptoms thought to be secondary to plasma cell infiltration and represents the majority of HHV8-negative “idiopathic” multicentric forms of the disease. Interestingly, patients with PC-UCD behave as PC-MCD, suggesting a stronger role of histology rather than Unicentric vs Multicentric phenotype in disease expression. We here studied the phenotype of HV-MCD, a rare subtype of CD characterized by hyaline-vascular pathological changes involving 2 or more lymph node stations. Methods: Patients were screened through the French national reference center for CD between January 1994 and June 2023. Cases were followed from first symptoms to last follow-up visit. Comparators consisted of patients with HV-UCD and patients with PC/Mixed iMCD (P/M-iMCD). All cases and biopsies were reviewed by three expert clinicians and one expert pathologist. Results: Sixteen patients with a diagnosis of HHV8-negative HV-MCD were identified. All patients had supra- and infradiaphragmatic involvement. Four were excluded because of a subsequent diagnosis of POEMS, systemic lupus erythematosus, tuberculosis, or inborn error of immunity. The 12 remaining patients were considered as having HV-iMCD and compared to 101 patients with P/M-iMCD and 139 patients with HV-UCD. Characteristics and comparison between the 3 groups are depicted in Table 1. When compared to HV-UCD, HV-iMCD displayed frequent systemic involvement with significantly higher ECOG, higher frequency of fever and splenomegaly, and higher levels of C-reactive protein, gammaglobulins, leukocytes and ferritinemia ( Figure 1). Age at diagnosis was not different between HV-UCD and HV-iMCD. No cases of TAFRO syndrome were observed in HV-UCD whereas 4 cases were observed in HV-iMCD. All cases of PNP (n=12) and FDCS (n=3) were observed in the HV-UCD group. We observed a younger age at diagnosis in HV-iMCD compared to P/M-iMCD (median 24 [range 13-70] vs median 50 [range 11-88] years respectively, p = 0.01). We also noted a trend towards lower levels of C reactive protein and gammaglobulins as well a higher albumin level in HV-iMCD vs P/M-iMCD but these differences were not significant ( Figure 1 and Table 1). Treatments were similar between HV-iMCD and P/M-iMCD with prescription of steroids or anti-IL6R as first line therapy in 8/12 (67%) and 61/101 (60%) respectively. As expected, surgery was the first line therapy in 98/139 (72%) of HV-UCD patients. One patient with HV-iMCD and two with HV-UCD died (logrank p = 0.10), whereas 13 died in the P/M-iMCD group (logrank p = 0.8). Conclusions: These data altogether indicate that HV-iMCD appears to be a distinct entity in CD landscape, sharing pathological aspects of HV-UCD and clinical/biological features of P/M iMCD. In line with this view, there seems to be no overlap between HV-UCD and HV-iMCD-related complications. The findings also suggest that nodal PC infiltration is not sufficient to explain the inflammatory pattern of iMCD.

3D Visualization of Whole Brain Vessels and Quantification of Vascular Pathology in a Chronic Hypoperfusion Model Causing White Matter Damage.

Chronic cerebral hypoperfusion is an important pathological factor in many neurodegenerative diseases, such as cerebral small vessel disease (CSVD). One of the most used animal models for chronic cerebral hypoperfusion is the bilateral common carotid artery stenosis (BCAS) mouse. For the therapy of CSVD and other diseases, it will be beneficial to understand the pathological alterations of the BCAS mouse, particularly vascular pathological changes. A mouse model of BCAS was used, and 8 weeks later, cognitive function of the mice was examined by using novel object recognition test and eight-arm radial maze test. 11.7 T magnetic resonance imaging (MRI) and luxol fast blue staining were used to evaluate the injury of the corpus callosum (CC), anterior commissure (AC), internal capsule (IC), and optic tract (Opt) in the cerebral white matter of mice. Three-dimensional vascular images of the whole brain of mice were acquired using fluorescence micro-optical sectioning tomography (fMOST) with a high resolution of 0.32 × 0.32 × 1.00 μm3. Then, the damaged white matter regions were further extracted to analyze the vessel length density, volume fraction, tortuosity, and the number of vessels of different internal diameters. The mouse cerebral caudal rhinal vein was also extracted and analyzed for its branch number and divergent angle in this study. BCAS modeling for 8 weeks resulted in impaired spatial working memory, reduced brain white matter integrity, and myelin degradation in mice, and CC showed the most severe white matter damage. 3D revascularization of the whole mouse brain showed that the number of large vessels was reduced and the number of small vessels was increased in BCAS mice. Further analysis revealed that the vessel length density and volume fraction in the damaged white matter region of BCAS mice were significantly reduced, and the vascular lesions were most noticeable in the CC. At the same time, the number of small vessels in the above white matter regions was significantly reduced, while the number of microvessels was significantly increased in BCAS mice, and the vascular tortuosity was also significantly increased. In addition, the analysis of caudal rhinal vein extraction revealed that the number of branches and the average divergent angle in BCAS mice were significantly reduced. The BCAS modeling for 8 weeks will lead to vascular lesions in whole brain of mice, and the caudal nasal vein was also damaged, while BCAS mice mainly mitigated the damages by increasing microvessels. What is more, the vascular lesions in white matter of mouse brain can cause white matter damage and spatial working memory deficit. These results provide evidence for the vascular pathological alterations caused by chronic hypoperfusion.

Placental Pathology and Maternal Risk Factors for Stillbirth: A Case-Control Study.

Background Fetal death is the delivery of a fetus with no sign of life, as indicated by the absence of breathing, heartbeat, pulsation of the umbilical cord, or definite movement of voluntary muscles. Nearly 2.6 million stillbirths are estimated to occur worldwide every year. Almost all of these (98%) stillbirths occur in low- and middle-income countries. About one-sixth of the stillbirths globally were recorded in India in 2019, making it the most burdened country in the world. In light of this, we conducted a study to identify the placental pathologies and maternal factors associated with stillbirth. Methodology A case-control study was conducted at the Department of Obstetrics & Gynecology, Veer Surendra Sai Institute of Medical Sciences and Research (VIMSAR), from June 2022 to May 2023. Cases included pregnant women with a gestational age of 28 weeks or more who delivered a stillbirth infant at VIMSAR, and controls included gestational age-matched deliveries with live birth. Consent to participate in the study was obtained before enrolment. The final sample size was 79 cases and controls. The chi-square test was performed for bivariate analysis, and logistic regression was used for multivariate analysis. Results In our study, we found a significant association between maternal age of more than 30 years (odds ratio (OR) = 3.01, 95% confidence interval (CI) = 1.91-4.22, p = 0.012), maternal education (with up to the primary level or less: OR = 6.19, 95% CI = 2.92-7.87, p = 0.012), history of addiction (tobacco chewing: OR = 5.58, 95% CI = 3.71-7.11, p = 0.03), and the number of antenatal visits (no visit: OR = 6.87, 95% CI = 2.91-7.79, p = 0.019) with an increased risk of stillbirth. Among the obstetrical complications, pre-eclampsia/eclampsia (OR = 3.87, 95% CI = 1.98-5.11, p = 0.001), premature rupture of membranes (PROM)/preterm premature rupture of the membranes (PPROM) (OR = 2.49, 95% CI = 1.31-3.91, p = 0.03) and antepartum hemorrhage (APH) (OR = 2.66, 95% CI = 1.65-3.58, p = 0.02) were found to be significantly related with stillbirth. Among placental pathologies, uteroplacental vascular pathology (OR = 7.39, 95% CI = 3.01-8.97), acute chorioamnionitis (OR = 3.35, 95% CI = 2.11-5.21), chronic inflammation (OR = 2.33, 95% CI = 1.91 4.17), calcific changes (OR = 4.46, 95% CI = 2.56-6.01), and retroplacental clots (OR = 9.95, 95% CI = 4.39-11.71) were associated with stillbirth. Conclusions In our study, advanced maternal age, absence of antenatal visits, low level of education, tobacco addiction, pre-eclampsia/eclampsia, APH, and PROM in pregnancy were the major risk factors associated with stillbirth. Uteroplacental vascular pathology, chorioamnionitis, chronic inflammation, retroplacental hematoma, and calcific changes were the most significant placental lesions associated with stillbirth.

Qingda granule ameliorates vascular remodeling and phenotypic transformation of adventitial fibroblasts via suppressing the TGF-β1/Smad2/3 pathway

Ethnopharmacological relevanceQingda granule (QDG) exhibits significant therapeutic effects on high blood pressure, vascular dysfunction, and elevated proliferation of vascular smooth muscle cells by inhibiting multiple pathways. However, the effects and underlying mechanisms of QDG treatment on hypertensive vascular remodeling are unclear. Aim of the studyThe aim of this study was to determine the role of QDG treatment in hypertensive vascular remodeling in vivo and in vitro. Materials and methodsAn ACQUITY UPLC I-Class system coupled with a Xevo XS quadrupole time of flight mass spectrometer was used to characterize the chemical components of QDG. Twenty-five spontaneously hypertensive rats (SHR) were randomly divided into five groups, including SHR (equal volume of double distilled water, ddH2O), SHR + QDG-L (0.45 g/kg/day), SHR + QDG-M (0.9 g/kg/day), SHR + QDG-H (1.8 g/kg/day), and SHR + Valsartan (7.2 mg/kg/day) groups. QDG, Valsartan, and ddH2O were administered intragastrically once a day for 10 weeks. For the control group, ddH2O was intragastrically administered to five Wistar Kyoto rats (WKY group). Vascular function, pathological changes, and collagen deposition in the abdominal aorta were evaluated using animal ultrasound, hematoxylin and eosin and Masson staining, and immunohistochemistry. Isobaric tags for relative and absolute quantification (iTRAQ) was performed to identify differentially expressed proteins (DEPs) in the abdominal aorta, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Cell Counting Kit-8 assays, phalloidin staining, transwell assays, and western-blotting were performed to explore the underlying mechanisms in primary isolated adventitial fibroblasts (AFs) stimulated with transforming growth factor-β 1 (TGF-β1) with or without QDG treatment. ResultsTwelve compounds were identified from the total ion chromatogram fingerprint of QDG. In the SHR group, QDG treatment significantly attenuated the increased pulse wave velocity, aortic wall thickening, and abdominal aorta pathological changes and decreased Collagen I, Collagen III, and Fibronectin expression. The iTRAQ analysis identified 306 DEPs between SHR and WKY and 147 DEPs between QDG and SHR. GO and KEGG pathway analyses of the DEPs identified multiple pathways and functional processes involving vascular remodeling, including the TGF-β receptor signaling pathway. QDG treatment significantly attenuated the increased cell migration, actin cytoskeleton remodeling, and Collagen I, Collagen III, and Fibronectin expression in AFs stimulated with TGF-β1. QDG treatment significantly decreased TGF-β1 protein expression in abdominal aortic tissues in the SHR group and p-Smad2 and p-Smad3 protein expression in TGF-β1-stimulated AFs. ConclusionsQDG treatment attenuated hypertension-induced vascular remodeling of the abdominal aorta and phenotypic transformation of adventitial fibroblasts, at least partly by suppressing TGF-β1/Smad2/3 signaling.

Effects of atorvastatin in suppressing pulmonary vascular remodeling in rats with chronic obstructive pulmonary disease

ObjectiveTo investigate the effects of atorvastatin calcium on pulmonary vascular remodeling, the authors explored the regulatory mechanism of Histone Deacetylation Enzyme-2 (HDAC2) in rats with Chronic Obstructive Pulmonary Disease (COPD), and provided a new direction for drug treatment in the progression of vascular remodeling. MethodsEighteen female SD rats were randomly divided into control (Group S1), COPD (Group S2), and atorvastatin calcium + COPD (Group S3) groups. A COPD rat model was established by passive smoking and intratracheal injection of Lipopolysaccharide (LPS). Haematoxylin and eosin staining and Victoria Blue + Van Gibson staining were used to observe pathological changes in the lung tissue. The pulmonary vascular inflammation score was calculated, and the degree of pulmonary vascular remodeling was evaluated. The ratio of Muscular Arteries in lung tissue (MA%), the ratio of the vessel Wall Area to the vessel total area (WA%), and the ratio of the vessel Wall Thickness to the vascular outer diameter (WT%) were measured using imaging software. The expression of HDAC2 was measured using western blotting, ELISA (Enzyme-Linked Immunosorbent Assay), and qPCR (Real-time PCR). ResultsCompared with the control group, the degree of pulmonary vascular inflammation and pulmonary vascular remodeling increased in rats with COPD. The WT%, WA%, and lung inflammation scores increased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissue decreased, and the level of Vascular Endothelial Growth Factor (VEGF) in the lung tissues increased (p < 0.05). Compared with the COPD group, the lung tissues from rats in the atorvastatin group had fewer inflammatory cells, and the vascular pathological changes were significantly relieved. The WT%, WA%, and lung inflammation scores decreased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissues increased, and the level of VEGF in the lung tissues decreased (p < 0.05). ConclusionThe present study revealed that atorvastatin calcium could regulate the contents and expression of HDAC2 in serum and lung tissues and inhibit the production of VEGF, thereby regulating pulmonary vascular remodeling in a rat model with COPD.

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases

BackgroundThis study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2.MethodsData originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein.ResultsThe mean age-at-death was 66.2 years (range: 26–97 years) and 14 were male. The patient’s medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein.ConclusionsAcute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach.

Rheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA. Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points. Twenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other. One-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.

Neutrophil extracellular traps accelerate vascular smooth muscle cell proliferation via Akt/CDKN1b/TK1 accompanying with the occurrence of hypertension.

Objective:Neutrophil extracellular traps (NETs) can trigger pathological changes in vascular cells or vessel wall components, which are vascular pathological changes of hypertension. Therefore, we hypothesized that NETs would be associated with the occurrence of hypertension.Methods:To evaluate the relationship between NETs and hypertension, we evaluated both the NETs formation in spontaneously hypertensive rats (SHRs) and the blood pressure of mice injected phorbol-12-myristate-13-acetate (PMA) via the tail vein to induce NETs formation in arterial wall. Meanwhile, proliferation and cell cycle of vascular smooth muscle cells (VSMCs), which were co-cultured with NETs were assessed. In addition, the role of exosomes from VSMCs co-cultured with NETs on proliferation signaling delivery was assessed.Results:Formation of NETs increased in the arteries of SHR. PMA resulted in up-regulation expression of citrullinated Histone H3 (cit Histone H3, a NETs marker) in the arteries of mice accompanied with increasing of blood pressure. NET treatment significantly increased VSMCs count and accelerated G1/S transition in vitro. Cyclin-dependent kinase inhibitor 1b (CDKN1b) was down-regulated and Thymidine kinase 1 (TK1) was up-regulated in VSMCs. Exosomes from VSMCs co-cultured with NETs significantly accelerated the proliferation of VSMCs. TK1 was up-regulated in the exosomes from VSMCs co-cultured with NETs and in both the arterial wall and serum of mice with PMA.Conclusion:NETs promote VSMCs proliferation via Akt/CDKN1b/TK1 and is related to hypertension development. Exosomes from VSMCs co-cultured with NETs participate in transferring the proliferation signal. These results support the role of NETs in the development of hypertension.

Histopathological features in advanced abdominal pregnancies co-infected with SARS-CoV-2 and HIV-1 infections: A case evaluation.

ObjectivesThis study aims to provide a semi-qualitative histopathological report of the dual SARS-CoV-2 and HIV infected placentae in the third trimester of Advanced Abdominal Pregnancy (AAP).Study designFour AAP placentae in the third trimester of pregnancy (two positive for HIV-1 and two positives for SARS-CoV-2) were histologically examined.ResultsThe SARS-CoV-2+ HIV+ placentae were dysmorphic in shape compared to the flattened disc-like shape noted in the SARS-CoV-2+HIV-, SARS-CoV-2-HIV+and SARS-CoV-2-HIV- placentae. Diffused syncytial knots and syncytial degeneration were observed in all placentae. Intermittent cytotrophoblast increase, perivillous and intravillous fibrin deposition, mononuclear inflammatory cells with widespread degeneration/necrosis of the syncytiotrophoblast and microcalcification were pronounced in the SARS-CoV-2+HIV+ compared to the SARS-CoV-2+HIV- placentae. Vascular pathological changes included thrombi, ectasis, mural hypertrophy and atherotic vessels.ConclusionElevated syncytial trophoblast injury, villitis, microcalcifications and mineralisation of the syncytial basement membrane in the AAP placentae may be due to SARS-CoV-2 viral transgression instead of HIV infection alone. Vascular malperfusion is suggestive of a hypoxic insult arising from a compensatory response to meet the fetal oxygen and nutrient demands of an AAP. Placentae from HIV infected women on antiretroviral treatment were characterised by vascular malperfusion.

Effects and Mechanisms of Taohong Siwu Decoction on the Prevention and Treatment of Myocardial Injury.

Taohong Siwu decoction (THSWD) is one of the classic prescriptions for promoting blood circulation and removing blood stasis. With the continuous in-depth excavation in basic and clinical research, it has been found that THSWD has made greater progress in the prevention and treatment of cardiovascular diseases. Mechanisms of the current studies have shown that it could prevent and treat the myocardial injury by inhibiting inflammatory reaction, antioxidant stress, inhibiting platelet aggregation, prolonging clotting time, anti-fibrosis, reducing blood lipids, anti-atherosclerosis, improving hemorheology and vascular pathological changes, regulating related signal pathways and other mechanisms to prevent and treat the myocardial injury, so as to protect cardiomyocytes and improve cardiac function. Many clinical studies have shown that THSWD is effective in the prevention and treatment of cardiovascular diseases related to myocardial injuries, such as coronary heart disease angina pectoris (CHD-AP), and myocardial infarction. In clinical practice, it is often used by adding and subtracting prescriptions, the combination of compound prescriptions and combinations of chemicals and so on. However, there are some limitations and uncertainties in both basic and clinical research of prescriptions. According to the current research, although the molecular biological mechanism of various active ingredients needs to be further clarified, and the composition and dose of the drug have not been standardized and quantified, this study still has exploration for scientific research and clinical practice. Therefore, this review mainly discusses the basic mechanisms and clinical applications of THSWD in the prevention and treatment of the myocardial injury caused by CHD-AP and myocardial infarction. The authors hope to provide valuable ideas and references for researchers and clinicians.

Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue.

Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking. A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14µmol/L) and 18 who had high plasma homocysteine levels (≥14µmol/L). Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature. Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function.

Apolipoprotein E genotypes modulate neuroinflammatory and vascular pathology in hyperhomocysteinemia‐induced VCID

Vascular contributions to cognitive impairment and dementia (VCID) are a major cause of dementia worldwide. Studies have shown Apolipoprotein E (ApoE) genotype is a risk factor for VCID in humans. Our lab has previously demonstrated recapitulation of aspects of human VCID using a hyperhomocysteinemia (HHcy)-inducing dietary model in mice. The goal of this study was to assess the impact of ApoE genotype on the vascular pathology and neuroinflammatory changes generated by the induction of HHcy.Humanized ApoE3/3 and 4/4 mice were aged to 6 months and placed onto an ad libitum diet of either HHcy inducing diet, or a nutritionally normal Control diet. The groups; E3/3 Control (n=14), E4/4 Control (n=15), E3/3 Folate (n=20), and E4/4 Folate (n=15); were balanced for sex. After 12 weeks on diet, tissue was harvested and assessed. Histological analyses for IBA-1, GFAP, and Prussian Blue were performed. RNA was extracted from frozen hippocampal tissue. We performed the NanoString Mouse Neuroinflammatory Panel, as well as qPCR for inflammatory genes and matrix metalloproteinases. Plasma and brain tissue were analyzed for homocysteine-relevant metabolites via LC-MS/MS.We observed significant differences in Iba1 between E3/3 HHcy and E4/4 HHcy groups, with E3/3 HHcy being more activated than the E4/4 HHcy. No differences in GFAP staining was observed between groups. Diet and ApoE genotype- dependent differences were also observed in a number of additional inflammatory genes, including TREM2, CD86, TNFa, and IL1b. Finally, metabolomics revealed a muted response to HHcy-inducing diet in the E4/4 mice compared to the E3/3 mice, suggesting altered homocysteine metabolism due to ApoE genotype.Our results demonstrate significant differences in how ApoE3/3 and ApoE4/4 mice respond to HHcy conditions on a pathological, gene expression, and metabolic level. Our neuroinflammatory data suggest that the ApoE4 mice were less reactive to neuroinflammatory stimulus than their ApoE3/3 counterparts.

Novel engineered, membrane‐tethered VEGF‐A variants promote formation of filopodia, proliferation, survival, and cord or tube formation by endothelial cells via persistent VEGFR2/ERK signaling and activation of CDC42/ROCK pathways

Therapeutic angiogenesis would be clinically valuable in situations such as peripheral vascular disease in diabetic patients and tissue reperfusion following ischemia or injury, but approaches using traditional isoforms of vascular endothelial growth factor-A (VEGF) have had little success. The isoform VEGF165 is both soluble and matrix-associated, but can cause pathologic vascular changes. Freely diffusible VEGF121 is not associated with pathologic angiogenesis, but its failure to remain in the vicinity of the targeted area presents therapeutic challenges. In this study, we evaluate the cellular effects of engineered VEGF variants that tether extracellular VEGF121 to the cell membrane with the goal of activating VEGF receptor 2 (VEGFR2) in a sustained, autologous fashion in endothelial cells. When expressed by primary human retinal endothelial cells (hRECs), the engineered, membrane-tethered variants eVEGF-38 and eVEGF-53 provide a lasting VEGF signal that induces cell proliferation and survival, increases endothelial permeability, promotes the formation of a cord/tube network, and stimulates the formation of elongated filopodia on the endothelial cells. The engineered VEGF variants activate VEGFR2, MAPK/ERK, and the Rho GTPase mediators CDC42 and ROCK, activities that are required for the formation of the elongated filopodia. The sustained, pro-angiogenic activities induced by eVEGF-38 and eVEGF-53support the potential of engineered VEGF variants-overexpressing endothelial cells as a novel combination of gene and cell-based therapeutic strategy for stimulating endothelial cell-autologous therapeutic angiogenesis.

Abstract 13462: Assessment of the Physiological and Pathological Structural Differences Along the Aorta in a Rat Model of Metabolic Syndrome

Introduction: Vascular geometry may vary along the aortic length in normal and chronic disease conditions such as metabolic syndrome. Aim: This study investigated regional structural changes in the aorta in a rodent model of metabolic syndrome, the high-fat diet streptozotocin-induced diabetes mellitus (HFD-D). Methods: Four-week-old male Wistar albino rats received a control diet (CD) or high fat diet (HFD) for 10 weeks. On week 6, 40 mg/kg streptozotocin and its buffer were injected intraperitoneally into the HFD and CD groups, respectively. Glucose and insulin tolerance tests (GTT and ITT) and tail-cuff systolic blood pressure (SBP) were measured. At the end of the study, rats were euthanized, and the thoracic and abdominal aortic segments collected for histomorphometric analysis of aortic media thickness, medial cross-sectional area (CSA), elastic lamellae number, interlamellar spacing, collagen density and lipid deposit density. Results: HFD-D rats showed elevated GTT, ITT and SBP. Abdominal aortic segments of both CD and HFD-D rats showed smaller media thickness and CSA, lower elastin lamellae number and higher collagen density compared with the thoracic segments, suggestive of physiological rather than pathological structural differences in both groups. Elastin interlamellar spacing and lipid plaque deposits were higher in the abdominal aorta of the HFD-D relative to controls, indicating that early vascular pathological changes favor the abdominal aorta in HFD-D rats. Conclusions: In this disease model of metabolic syndrome, vascular structural changes are differentially expressed along the aorta, with pathological features limited to the abdominal rather than the thoracic aorta. These structural abnormalities may underlie the elevated blood pressure seen in this model and potential progression to hypertensive cardiovascular disease.

Ultrasmall superparamagnetic iron oxide nanoparticles: A next generation contrast agent for magnetic resonance imaging.

As a research hotspot, the development of magnetic resonance imaging (MRI) contrast agents has attracted great attention over the past decades for improving the accuracy of diagnosis. Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles with core diameter smaller than 5.0nm are expected to become a next generation of contrast agents owing to their excellent MRI performance, long blood circulation time upon proper surface modification, renal clearance capacity, and remarkable biosafety profile. On top of these merits, USPIO nanoparticles are used for developing not only T1 contrast agents, but also T2 /T1 switchable contrast agents via assembly/disassembly approaches. In recent years, as a new type of contrast agents, USPIO nanoparticles have shown considerable applications in the diagnosis of various diseases such as vascular pathological changes and inflammations apart from malignant tumors. In this review, we are focusing on the state-of-the-art developments and the latest applications of USPIO nanoparticles as MRI contrast agents to discuss their advantages and future prospects. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Role of miR-134 in angiotensin II-induced vascular cell pathological changes in atherosclerosis

Purpose: To investigate the role of miR-134 in vascular smooth muscle cell dysfunction-related cardiovascular disease.&#x0D; Methods: The effect of miR-134 was evaluated after human aortic smooth muscle cells (HASMCs) were transfected with miR-134 mimics. The expression levels of p-Akt, mechanistic target of rapamycin (mTOR), cleaved caspase-3, p53, and β-actin were evaluated by immunoblotting. Terminal deoxynucleotidyl transferase dUTP nick-end labeling was used to measure cell apoptosis. Reactive oxygen species levels were assayed by fluorescence microscopy after staining with 2’,7’– dichlorofluorescein diacetate.&#x0D; Results: Angiotensin II treatment induced miR-134 expression and Akt/mTOR activation, and inhibited cell viability in HASMCs (p &lt; 0.01). Co-treatment with miRNA-134 reversed Ang II-induced HASMC dysfunction (p &lt; 0.01). Overexpression of miR-134 is protective in Ang II-induced oxidative stress and apoptosis via the Akt/mTOR pathway (p &lt; 0.05).&#x0D; Conclusion: MicroRNA-134 in HASMCs is a potential therapeutic target for preventing Ang II-induced cardiac dysfunction via modulating Akt/mTOR pathway.

Potential Role of Macrophage Phenotypes and CCL2 in the Pathogenesis of Takayasu Arteritis.

ObjectivesTo investigate vascular macrophage phenotype as well as vascular and peripheral chemokine (C-C motif) ligand 2 (CCL2) expression during different stages of disease progression in patients with Takayasu Arteritis (TA).MethodsIn this study, 74 patients with TA and 50 controls were recruited. TA disease activity was evaluated with Kerr scores. Macrophage phenotype and CCL2 expression were examined by immunohistochemistry in vascular specimens from 8 untreated and 7 treated TA patients, along with 4 healthy controls. Serum CCL2 were quantified by enzyme-linked immune-absorbent assay from TA patients at baseline (n=59), at 6-months (n=38), and from 46 healthy volunteers. Vascular macrophage phenotype, vascular CCL2 expression and serum CCL2 levels during different stages, as well as the relationship between serum CCL2 and disease activity or other inflammatory parameters (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin 6 (IL-6)) were investigated.ResultsIn untreated patients, vascular M1 macrophages and CCL2 showed increased expression, mainly in the adventitia. In contrast, in treated patients, vascular adventitial M1 and CCL2 expression were decreased, while vascular medial M2 macrophages and CCL2 levels were increased. Distribution of macrophages and CCL2 was consistent within the TA vascular lesions regardless of the disease stage. Furthermore, peripheral CCL2 was elevated in patients with TA (TA: 160.30 ± 120.05 vs. Control: 65.58 ± 54.56 pg/ml, P < 0.001). CCL2 levels were found to correlate with ESR, CRP, and IL-6 (all R values between 0.55 and 0.6, all P < 0.001). Receiver operating curve analysis demonstrated that CCL2 (at the cut-off value of 100.36 pg/ml) was able to predict disease activity (area under the curve = 0.74, P = 0.03). Decrease in CCL2 level was observed in patients with clinical remission (CR), but not in patients without CR, after 6 months of treatment (CR patients: baseline 220.18 ± 222.69 vs. post-treatment 88.71 ± 55.89 pg/ml, P = 0.04; non-CR patients: baseline 142.45 ± 104.76 vs. post-treatment 279.49 ± 229.46 pg/ml, P = 0.02).ConclusionsMacrophages contribute to vascular pathological changes in TA by undergoing phenotype transformation. CCL2 is an important factor for recruiting macrophages and a potential biomarker for disease activity.