Vascular Degeneration Research Articles

Impacts of Telomeric Length, Chronic Hypoxia, Senescence, and Senescence-Associated Secretory Phenotype on the Development of Thoracic Aortic Aneurysm

Thoracic aortic aneurysm (TAA) is an age-related and life-threatening vascular disease. Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and telomeric DNA damage on cellular homeostasis and vascular degeneration of TAA. We analyzed healthy and aortic aneurysm specimens (215 samples) for telomere length (TL), chronic DNA damage, and resulting changes in cellular homeostasis, focusing on senescence and apoptosis. Compared with healthy thoracic aorta (HTA), patients with tricuspid aortic valve (TAV) showed telomere shortening with increasing TAA size, in contrast to genetically predisposed bicuspid aortic valve (BAV). In addition, TL was associated with chronic hypoxia and telomeric DNA damage and with the induction of senescence-associated secretory phenotype (SASP). TAA-TAV specimens showed a significant difference in SASP-marker expression of IL-6, NF-κB, mTOR, and cell-cycle regulators (γH2AX, Rb, p53, p21), compared to HTA and TAA-BAV. Furthermore, we observed an increase in CD163+ macrophages and a correlation between hypoxic DNA damage and the number of aortic telocytes. We conclude that chronic hypoxia is associated with telomeric DNA damage and the induction of SASP in a diseased aortic wall, promising a new therapeutic target.

Three‐dimensional study on morphological changes of arterioles in Cerebral Amyloid Angiopathy

AbstractBackgroundThe accumulation of β‐amyloid plaques in the brain is a hallmark of Alzheimer’s disease. Vascular involvement is also common in the form of cerebral amyloid angiopathy (CAA), a vasculopathy that is produced when the β‐amyloid forms toxic deposits on vessels wall. The accumulation of β‐amyloid makes blood vessels stiff and increases the thickness of the vessel wall, reducing the blood flow and energy supply for the tissue. This predisposes to hemorrhage and contribute to cognitive decline and stroke.MethodWe used the CLARITY method to analyze tissue samples from patients with CAA to characterize changes to vessel morphology associated with vascular degeneration. The blood vessels were stained with isolectin, β‐amyloid with thiazine red, and proteins with primary antibodies associated with the vascular structure. We conducted 3D microscopy using a light sheet microscope and performed surface volume reconstruction to assess the morphology of rupturing vessel. We also measured arteriolar stiffness of vessels damaged using atomic force microscopy (AFM). Finally, we assessed cerebral blood flow and autoregulation in vivo in a novel mouse model of CAA using laser speckle flowetry.ResultVessels with CAA demonstrate an organized ring‐shaped deposits β‐amyloid. At sites, these rings are shattered and the vessel diameter increase. Degenerating vessels also demonstrate depletion of vascular smooth muscle, circumferential luminal dilation, and thickening of the vessel wall. Lysyl oxidase levels and markers of fibrosis are increased in vessels with degenerating features. We found that the arteriolar wall was more than 400% stiffer in CAA than in arterioles without CAA in the mice model. Finally, in a novel mouse model of CAA we are terming the VASC‐FAD model, resting cerebral blood flow and vasoreactivity are both reduced.ConclusionCombining the CLARITY technique associated with surface volume rendering and AFM we have a better overview of microhemorrhages to understand the vascular fragility and morphological changes, and accumulation of myofibroblast markers caused by the β‐amyloid deposition and stiffness. These features combine to alter the physiology of cerebral blood flow. Defining mechanism of microvascular degeneration in AD and CAA may lead to novel treatment targets to restore the ECM and vascular network integrity.

Endothelial LRP1-ICD Accelerates Cognition-Associated Alpha-Synuclein Pathology and Neurodegeneration through PARP1 Activation in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and accumulation of misfolded alpha-synuclein (αSyn) into Lewy bodies. In addition to motor impairment, PD commonly presents with cognitive impairment, a non-motor symptom with poor outcome. Cortical αSyn pathology correlates closely with vascular risk factors and vascular degeneration in cognitive impairment. However, how the brain microvasculature regulates αSyn pathology and neurodegeneration remains unclear. Here, we constructed a rapidly progressive PD model by injecting alpha-synuclein preformed fibrils (αSyn PFFs) into the cerebral cortex and striatum. Brain capillaries in mice with cognitive impairment showed a reduction in diameter and length after 6months, along with string vessel formation. The intracellular domain of low-density lipoprotein receptor-related protein-1 (LRP1-ICD) was upregulated in brain microvascular endothelium. LRP1-ICD promoted αSyn PFF uptake and exacerbated endothelial damage and neuronal apoptosis. Then, we overexpressed LRP1-ICD in brain capillaries using an adeno-associated virus carrying an endothelial-specific promoter. Endothelial LRP1-ICD worsened αSyn PFF-induced vascular damage, αSyn pathology, or neuron death in the cortex and hippocampus, resulting in severe motor and cognitive impairment. LRP1-ICD increased the synthesis of poly(adenosine 5'-diphosphate-ribose) (PAR) in the presence of αSyn PFFs. Inhibition of PAR polymerase 1 (PARP1) prevented vascular-derived injury, as did loss of PARP1 in the endothelium, which was further implicated in endothelial cell proliferation and inflammation. Together, we demonstrate a novel vascular mechanism of cognitive impairment in PD. These findings support a role for endothelial LRP1-ICD/PARP1 in αSyn pathology and neurodegeneration, and provide evidence for vascular protection strategies in PD therapy.

Short-Term Omega-3 Supplementation Modulates Novel Neurovascular and Fatty Acid Metabolic Proteome Changes in the Retina and Ophthalmic Artery of Mice with Targeted Cyp2c44 Gene Deletion.

Cytochrome P450 (CYP) gene mutations are a common predisposition associated with glaucoma. Although the molecular mechanisms are largely unknown, omega-3 polyunsaturated fatty acids (ω-3 PUFA) and their CYP-derived bioactive mediators play crucial roles in the ocular system. Here, we elucidated the proteome and cell-signalling alterations attributed to the main human CYP2C gene deficiency using a homologous murine model (Cyp2c44-/-), and unravelled the effects of acute ω-3 PUFA supplementation in two ocular vascular beds comprising the retrobulbar ophthalmic artery (OA) and retina (R). Male Cyp2c44-/- mice (KO) and their floxed littermates (WT) were gavaged daily for 7 days with 0.01 mL/g of ω-3 PUFA composed of menhaden fish oil. Another group in respective strains served as vehicle-treated controls. OA and R were isolated at day 8 post-treatment (n = 9/group) and subjected to mass spectrometry (MS)-based proteomics and in silico bioinformatics analyses. Cyp2c44-/- resulted in significant detrimental proteome changes associated with compromised vascular integrity and degeneration in the OA and R, respectively. However, notable changes in the OA after ω-3 PUFA intake were associated with the maintenance of intercellular junctional and endothelial cell functions, as well as activation of the fatty acid metabolic pathway in the KO mice. Conversely, ω-3 PUFA supplementation profoundly influenced the regulation of a large majority of retinal proteins involved in the preservation of neuronal and phototransduction activities in WT mice, namely synaptophysin, phosducin and guanylate cyclase-1, while significantly abrogating degenerative processes in the KO mice via the regulation of, namely, synaptotagmin-1 and beta-crystallin B2. In gist, this study demonstrated that dietary supplementation with ω-3 PUFA for a short period of seven days regulated specific neuro-vasculoprotective mechanisms to preserve the functionality of the OA and R in the absence of Cyp2c44. The potential adjunct use of ω-3 PUFA for glaucoma therapy needs further investigation.

Inhibition of CD40-TRAF6-dependent inflammatory activity halts the onset of diabetic retinopathy in streptozotocin-diabetic mice

Diabetes initiates inflammation that can impair the retinal vasculature, and lead to diabetic retinopathy; one of the leading causes of blindness. Inflammatory pathways have been examined as potential therapeutic targets for diabetic retinopathy, but there is still a need for early-stage treatments. We hypothesized that the CD40-TNF Receptor Associated Factor 6 (TRAF6) axis plays a pivotal role in the onset of diabetic retinopathy, and that the CD40-TRAF6 axis would be a prime therapeutic target for early-stage non-proliferative diabetic retinopathy. The CD40-TRAF6 complex can initiate NFκB activation, inflammation, and tissue damage. Further, CD40 and TRAF6 are constitutively expressed on Muller glia, and upregulated in the diabetic retina. Yet the role of the CD40-TRAF6 complex in the onset of diabetic retinopathy is still unclear. In the current study, we examined the CD40-TRAF6 axis in diabetic retinopathy using a small molecule inhibitor (SMI-6877002) on streptozotocin-induced diabetic mice. When CD40-TRAF6-dependent inflammation was inhibited, retinal vascular leakage and capillary degeneration was ameliorated in diabetic mice. Collectively, these data suggest that the CD40-TRAF6 axis plays a pivotal role in the onset of diabetic retinopathy, and could be a novel therapeutic target for early diabetic retinopathy.

MicroRNA-150 (miR-150) and Diabetic Retinopathy: Is miR-150 Only a Biomarker or Does It Contribute to Disease Progression?

Diabetic retinopathy (DR) is a chronic disease associated with diabetes mellitus and is a leading cause of visual impairment among the working population in the US. Clinically, DR has been diagnosed and treated as a vascular complication, but it adversely impacts both neural retina and retinal vasculature. Degeneration of retinal neurons and microvasculature manifests in the diabetic retina and early stages of DR. Retinal photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. Chronic inflammation is a hallmark of diabetes and a contributor to cell apoptosis, and retinal photoreceptors are a major source of intraocular inflammation that contributes to vascular abnormalities in diabetes. As the levels of microRNAs (miRs) are changed in the plasma and vitreous of diabetic patients, miRs have been suggested as biomarkers to determine the progression of diabetic ocular diseases, including DR. However, few miRs have been thoroughly investigated as contributors to the pathogenesis of DR. Among these miRs, miR-150 is downregulated in diabetic patients and is an endogenous suppressor of inflammation, apoptosis, and pathological angiogenesis. In this review, how miR-150 and its downstream targets contribute to diabetes-associated retinal degeneration and pathological angiogenesis in DR are discussed. Currently, there is no effective treatment to stop or reverse diabetes-caused neural and vascular degeneration in the retina. Understanding the molecular mechanism of the pathogenesis of DR may shed light for the future development of more effective treatments for DR and other diabetes-associated ocular diseases.

Resveratrolün sıçan böbreğinde cisplatine bağlı hasar üzerindeki koruyucu etkisi

Purpose: The aim of this study was to evaluate the protective effect of resveratrol on cisplatin induced damage in rat kidney.
 Materials and Methods: 30 female Wistar-Albino rats were allocated to form three groups: In group 1 (control group), 1 mL of 0.9% NaCl (saline) was administered intraperitoneally for 3 days. In group 2 (cisplatin group), 7.5 mg / kg intraperitoneal cisplatin was given for 3 days. In group 3 (cisplatin + resveratrol group) 7.5 mg / kg cisplatin and 10 mg / kg resveratrol were given via intraperitoneal route. Right kidneys were surgically extirpated in all groups. Malondialdehyde (MDA) levels and activities of catalase (CAT) and superoxide dismutase (SOD) were measured in both blood and tissues. Also, toxicity markers such as vascular congestion, hemorrhage, tubule degeneration and glomerular damage were assessed by examining the slides prepared from kidney tissue with microscopy.
 Results: Tissue damage was significantly higher in group 2 than other groups. The MDA levels were significantly higher and the activities of SOD, and CAT were lower in group 2 than other groups. 
 Conclusion: According to our short term findings, resveratrol might be an effective molecule to prevent the harmful effect of cisplatin in rat kidney.

The effect of Lactobacillus casei and Bacillus coagulans probiotics on liver damage induced by silver nanoparticles and expression of Bax, Bcl2 and Caspase 3 genes in male rats.

In this study, we aimed to evaluate the effect of Bacillus coagulans and Lactobacillus casei probiotics on liver damage induced by silver nanoparticles and expression of Bax, Bcl2 and Caspase 3 genes in rats. 32 adult male Wistar rats were divided into four healthy groups (control), the group receiving silver nanoparticles treated with L. casei, the group receiving silver nanoparticles treated with B. coagulans and the group receiving only silver nanoparticles. The effect of nanoparticles was induced by intraperitoneal injection of silver nanoparticles prepared from nettle at a dose of 50 mg/kg and entered the liver tissue through the bloodstream. Two days after injection, probiotic treatment with 109 CFU was performed by gavage for 30 days. One day after the last gavage, rat liver tissue weight was assessed. Also, the total amount of RNA was extracted from treated, and healthy tissues, as well as induced silver nanoparticles tissues, then evaluated by Real Time PCR. Data were evaluated using one-way Anova, Tukey test. Based on the biochemical results of this study, exposure of rats to different concentrations of silver nanoparticles compared with the control group caused a significant increase in the serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), especially at high concentrations. Evaluation of damage and histopathological lesions showed that silver nanoparticles in different concentrations caused different damage to liver tissue, so that, necrosis, inflammatory cell infiltration and vascular degeneration were observed at different concentrations by silver nanoparticles. In the present study, the effects of L. casei cell extract on increasing the expression of Bax proapoptotic gene and decreasing Bcl2 gene expression in cancer cells and inducing programmed cell death were shown. In this study, the expression of Bax, Bcl-2 and Caspase-3 genes in the group receiving silver nanoparticles and in the groups treated with probiotics showed significant changes compared to the control group. It can be concluded that the function of silver nanoparticles and the effects of relative improvement of probiotics are from the internal route of apoptosis and factors such as dose, nanoparticle size and nanoparticle coating have an important role in the toxicity of silver nanoparticles, thus the destructive effects on liver tissue could be increased by increasing the concentration of silver nanoparticles.

Longitudinal characterization of retinal vasculature alterations with optical coherence tomography angiography in a mouse model of tauopathy

Tauopathies are a family of neurodegenerative diseases which predominately afflict the rapidly growing aging population suffering from various brain disorders including Alzheimer's disease, frontotemporal dementia with parkinsonism-17 and Pick disease. As the only visually accessible region of the central nervous system, in recent years, the retina has attracted extensive attention for its potential as a target for visualizing and quantifying emerging biomarkers of neurodegenerative diseases. Our previous study has found that retinal vascular inflammation and leakage occur at the very early stage of tauopathic mouse model. Here, we aimed to non-invasively visualize age-dependent alterations of retinal vasculature assessing the potential for using changes in retinal vasculature as the biomarker for the early diagnosis of tauopathy. Optical coherence tomography angiography (OCTA), a non-invasive depth-resolved high-resolution imaging technique was used to visualize and quantify tauopathy-induced alterations of retinal vasculature in P301S transgenic mice overexpressing the P301S mutant form of human tau and age-matched wild type littermate mice at 3, 6 and 10 months of age. We observed significant alterations of vascular features in the intermediate capillary plexus (ICP) and deep capillary plexus (DCP) but not in the superficial vascular complex (SVC) of P301S mice at early stages of tauopathy. With aging, alterations of vascular features in P301S mice became more prominent in all three vascular plexuses. Staining of retinal vasculature in flatmounts and trypsin digests of P301S mice at 10 months of age revealed decreased vessel density and increased acellular capillary formation, indicating that vascular degeneration also occurs during tauopathy. Overall, our results demonstrate that the changes in retinal vascular features accelerate during the progression of tauopathy. Vessels in the ICP and DCP may be more susceptible to tauopathy than vessels in the SVC. Since changes in retinal vasculature often precede tau pathology in the brain, non-invasive identification of retinal vascular alterations with OCTA may be a useful biomarker for the early diagnosis of tauopathy and monitoring its progression.

Clerodendrum wallichii Merr Methanol Extract Protected Alcohol-Induced Liver Injury in Sprague-Dawley Rats by Modulating Antioxidant Enzymes.

Materials and Methods An oral acute toxicity study was carried out following OECD guidelines. Hepatotoxicity was induced by the administration of ethanol for 4 weeks. Hepatic enzymes and oxidative stress biomarkers were determined using commercial diagnostic kits. Results Treatment of rats with MECW (800 mg/kg) showed the highest reduction of body weight (4.76 ± 0.372 vs. 16.92 ± 0.846) and liver weight (3.06 ± 0.128 vs 5.55 ± 0.311). Treatment of rats with MECW at 200, 400, 600, 800, and 1000 mg/kg significantly (∗∗p < 0.01) reduced SGPT. Similarly, serum SGOT and ALP were significantly decreased by MECW (200, 400, 600, 800, and 1000 mg/kg). All used doses of MECW significantly increased antioxidant enzymes GSH and SOD. MECW (600 and 800 mg/kg) significantly promoted CAT levels in liver tissues; whereas, it significantly diminished oxidative biomarker, MDA. Histopathological observations of the liver showed improvement in the architecture of hepatic cells having signs of protection with a reduced number of inflammatory cells, vascular degeneration and congestion, cellular degeneration, necrosis, and significant reduction of fatty cells accumulation. Acute toxicity study resulted in the well-tolerability and safety of used doses of MECW (200–1000 mg/kg) in rats. Conclusion Our study clearly demonstrated the hepatoprotective effect of Clerodendrum wallichii extract against ethanol-induced liver injury in the laboratory rats model.

Nanoparticles and nanomaterials as inevitable modern toxic agents. Review. Part 3. Influence of nanoparticles on brain and behavior. Conclusions and unsolved problems

The final part of the review focuses on the existing methods and results of studying the effects of nanoparticles (NPs) on the brain and behavior. The types of behavioral tests used to assess changes in the behavior of NP-treated animals are described. The data accumulated in the literature on the negative influence of NPs on animal brains exposed to NPs in adulthood are considered. The signs of different cellular and tissue damage are presented, such as development of oxidative stress in the brain, inflammation and swelling, disturbances in the structure of cells, and an increase in the permeability of the bloodbrain barrier. Disturbances in spatial memory, working, and long-term reference memory, decreased propensity for social interactions, inhibition of exploratory behavior, depression and anxiety, and impaired motor coordination, were found after various types and duration of contact of animals with NPs. The accumulated information about the negative consequences of prenatal and early postnatal, during lactation, for example, contact with NPs for mature offspring, is also described. Various cellular and tissue damage is found in the brain of young animals, such as the inhibition of cell proliferation, an increase in the number of cells undergoing apoptosis, edema and vascular degeneration, a decrease in the expression of genes associated with neurogenesis, and numerous signs of the development of oxidative stress. Behavioral disturbances in adult animals that had contact with NPs in early ontogenesis are considered, such as manifestations of depressive behavior or increased anxiety and suppression of spatial and short-term memory. Contradictory results of studies about contact with NPs in both adulthood and early ontogenesis are also presented. In conclusion, unresolved issues are highlighted, and general conclusions on the review are given.

Nano Zinc Supplementation Affects Immunity, Hormonal Profile, Hepatic Superoxide Dismutase 1 (SOD1) Gene Expression and Vital Organ Histology in Wister Albino Rats.

The study was conducted to assess nano zinc (ZnN) as a feed supplement with an aim to compare the supplemental dose of inorganic zinc (ZnI). ZnN was synthesized from 0.45molar (M) zinc nitrate [Zn(NO3)2.6H2O] and 0.9M sodium hydroxide (NaOH) and was confirmed to be of ZnN by TEM-EDAX measurements. Wister albino rats (rats; 84, 53.6 ± 0.65g) were divided into seven groups (4 replicate with 3 rats each) and given feed supplemented with zinc for 60days with either of the following diets: (1) normal control (NC): basal diet (BD) + no supplemental Zn; (2) ZnI-25: BD + 25mg/kg Zn from inorganic ZnO; (3) ZnN-25: BD + 25mg/kg of ZnN; (4) ZnN-12.5: BD + 12.5mg/kg of ZnN; (5) ZnN-6.25: BD + 6.25mg/kg of ZnN; (6) ZnN-3.125: BD + 3.125mg/kg of ZnN; (7) ZnN-50: BD + 50mg/kg of ZnN. T3 and insulin-like growth factor-1 (IGF-1) hormone levels were similar among groups (P > 0.05), whereas T4 and testosterone were significantly affected, based on supplemented dose. Zn supplementation improved both cell-mediated and humoral immunity. However, both cell-mediated immunity at 24h and humoral immunity were statistically similar in ZnI-25 and ZnN-6.25 groups. Superoxide dismutase 1 gene expression was found to be similar in all experimental groups. The vascular degeneration were found in liver tissues moderately in NC, mildly in ZnN-6.25 and ZnN-3.125 groups, and no observable changes were noticed in kidney and spleen tissues. However, there was a mild damage in intestinal epithelium of ZnN-25 group rats, hyperplasia of goblet cells, and moderate damage in intestinal villi were observed in ZnN-50 group rats. From the study, it can be concluded that ZnN at half the dose of ZnI showed similar or better responses in terms of immunity, SOD-1 expression, hormonal profiles, and the tissue architecture of vital organs in rats, i.e., 25mg/kg of Zn from ZnI and 12.5mg/kg of ZnN impacted similar biological responses like immunity, SOD-1 expression, hormonal profiles, and the tissue architecture of vital organs in rats.

MiR-335-5p regulates the proliferation, migration and phenotypic switching of vascular smooth muscle cells in aortic dissection by directly regulating SP1.

Uncontrolled proliferation, migration and phenotypic switching of vascular smooth muscle cells (VSMCs) are important steps in the development and progression of aortic dissection (AD). The function and potential mechanism of miR-335-5p in the pathogenesis of AD are explored in this study. Specifically, the biological function of miR-335-5p is explored in vitro through CCK-8, Transwell, immunofluorescence, EdU, wound-healing, RT-qPCR and western blotting assays. In addition, an AD model induced by angiotensin II is used to investigate the function of miR-335-5p in vivo. A dual-luciferase assay is performed to verify the targeting relationship between miR-335-5p and specificity protein 1 (SP1). Experiments involving the loss of SP1 function are performed to demonstrate the function of SP1 in the miR-335-5p-mediated regulation of human aortic-VSMCs (HA-VSMCs). AD tissues and platelet-derived growth factor BB (PDGF-BB)-stimulated HA-VSMCs show significant downregulation of miR-335-5p expression and upregulated SP1 expression. Overexpression of miR-335-5p effectively suppresses cell proliferation, migration and synthetic phenotype markers and enhances contractile phenotype markers induced by PDGF-BB treatment. Additionally, SP1 is identified as a target gene downstream of miR-335-5p, and its expression is negatively correlated with miR-335-5p in AD. Upregulation of SP1 partially reverses the inhibitory effect of miR-335-5p on HA-VSMCs, whereas the downregulation of SP1 has the opposite effect. Furthermore, Ad-miR-335-5p clearly suppresses aorta dilatation and vascular media degeneration in the AD model. Our results suggest that miR-335-5p inhibits HA-VSMC proliferation, migration and phenotypic switching by negatively regulating SP1, and indicate that miR-335-5p may be a potential therapeutic target in AD.

Neuroprotective Effects of Tauroursodeoxicholic Acid Involves Vascular and Glial Changes in Retinitis Pigmentosa Model.

PurposeRetinitis pigmentosa is primarily characterized by a massive photoreceptor loss. But a global retinal remodeling occurs in later stages of the disease. At that phase, glial cells and retinal vasculature are also strongly affected. The main aim of the present work is to assess if the bile acid Tauroursodeoxicholic acid (TUDCA), which has a demonstrated neuroprotective effect in numerous neurodegenerative diseases, is able to prevent glial and vascular degeneration in the P23H rat retina.MethodsHomozygous P23H (line 3) animals were injected weekly with a TUDCA (500 mg/kg, i.p.) or vehicle solution, from the postnatal day (P) 21 to P120. Sprague-Dawley rats (SD) were used as control. Retinal cross-sections and wholemounts were immunostained using different glial and vascular markers and visualized with confocal microscopy. Retinal blood vessels were stained with nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry and retinal vascular networks were drawn by hand using a camera lucida.ResultsAt P120, the photoreceptor degeneration observed in P23H rats was accompanied by a reduction in the vascular network density and complexity at the deep capillary plexus. In addition, astrocytes showed gliotic features and the outer processes of Müller cells displayed an aberrant distribution in ring-shaped structures. When treated with TUDCA, P23H rats displayed better-preserved vessels and capillary loops in the deep capillary plexus which are associated with the partial preservation of photoreceptors. TUDCA treatment also increased the number of astrocytes and reduced the presence of Müller cell process clusters in the outer retina.ConclusionThis work suggests that, besides its neuroprotective effect on photoreceptor cells, TUDCA treatment also protects from vascular and glial degeneration, a fact that encourages the use of TUDCA as a powerful therapy for neurodegenerative diseases.

Thoracoabdominal aortic aneurysm in connective tissue disorder patients.

Connective tissue disorders (CTDs) are a group of genetically triggered diseases in which the primary defect involves collagen and elastin protein assembly with potential vascular degenerations such as thoracoabdominal aortic aneurysm (TAAA) and dissection. These most commonly include Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm and dissection. Open surgical repair represents the standard approach in this specific group of patients. Extensive aortic replacements are generally performed in order to reduce long-term complications caused by the progressive dilatation of the remnant aortic segments. In the last decades, endovascular interventions have emerged as a valid alternative in patients affected by degenerative TAAA. However, in patients with CTD, this approach presents higher rates of reinterventions and postoperative complications with a disputable long-term durability, and it is nowadays performed for very selective indications such as severe comorbidities and urgent/emergent settings. Despite a deeper knowledge of the pathophysiological mechanisms involved in CTD, improvements in medical therapy, and a multidisciplinary approach fully involved in the management of these usually frailer patients, this specific group still represents a challenge. Further dedicated studies addressing mid-term and long-term outcomes in this selected population are needed.

Vascular mapping of the human hippocampus using Ferumoxytol-enhanced MRI

The hippocampus is a small but complex grey matter structure that plays an important role in spatial and episodic memory and can be affected by a wide range of pathologies including vascular abnormalities. In this work, we introduce the use of Ferumoxytol, an ultra-small superparamagnetic iron oxide (USPIO) agent, to induce susceptibility in the arteries (as well as increase the susceptibility in the veins) to map the hippocampal micro-vasculature and to evaluate the quantitative change in tissue fractional vascular density (FVD), in each of its subfields. A total of 39 healthy subjects (aged 35.4 ± 14.2 years, from 18 to 81 years old) were scanned with a high-resolution (0.22×0.44×1 mm3) dual-echo SWI sequence acquired at four time points during a gradual increase in Ferumoxytol dose (final dose = 4 mg/kg). The volumes of each subfield were obtained automatically from the pre-contrast T1-weighted data. The dynamically acquired SWI data were co-registered and adaptively combined to reduce the blooming artifacts from large vessels, preserving the contrast from smaller vessels. The resultant SWI data were used to segment the hippocampal vasculature and to measure the FVD ((volume occupied by vessels)/(total volume)) for each subfield. The hippocampal fissure, along with the fimbria, granular cell layer of the dentate gyrus and cornu ammonis layers (except for CA1), showed higher micro-vascular FVD than the other parts of hippocampus. The CA1 region exhibited a significant correlation with age (R = −0.37, p < 0.05). demonstrating an overall loss of hippocampal vascularity in the normal aging process. Moreover, the vascular density reduction was more prominent than the age correlation with the volume reduction (R = −0.1, p > 0.05) of the CA1 subfield, which would suggest that vascular degeneration may precede tissue atrophy.

Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.

The development of thoracic aortic dissection (TAD) is closely related to extracellular matrix degradation and vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type. LGMN (legumain) degrades extracellular matrix components directly or by activating downstream signals. The role of LGMN in VSMC differentiation and the occurrence of TAD remains elusive. Microarray datasets concerning vascular dissection or aneurysm were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes. Four-week-old male Lgmn knockout mice (Lgmn-/-), macrophage-specific Lgmn knockout mice (LgmnF/F;LysMCre), and RR-11a-treated C57BL/6 mice were given BAPN (β-aminopropionitrile monofumarate; 1 g/kg/d) in drinking water for 4 weeks for TAD modeling. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Cell interaction was examined in macrophage and VSMC coculture system. The reciprocity of macrophage-derived LGMN with integrin αvβ3 in VSMCs was tested by coimmunoprecipitation assay and colocalization analyses. Microarray datasets from the Gene Expression Omnibus database indicated upregulated LGMN in aorta from patients with TAD and mice with angiotensin II-induced AAA. Elevated LGMN was evidenced in aorta and sera from patients with TAD and mice with BAPN-induced TAD. BAPN-induced TAD progression was significantly ameliorated in Lgmn-deficient or inhibited mice. Macrophage-specific deletion of Lgmn alleviated BAPN-induced extracellular matrix degradation. Unbiased profiler polymerase chain reaction array and Gene Ontology analysis displayed that LGMN regulated VSMC phenotype transformation. Macrophage-specific deletion of Lgmn ameliorated VSMC phenotypic switch in BAPN-treated mice. Macrophage-derived LGMN inhibited VSMC differentiation in vitro as assessed by macrophages and the VSMC coculture system. Macrophage-derived LGMN bound to integrin αvβ3 in VSMCs and blocked integrin αvβ3, thereby attenuating Rho GTPase activation, downregulating VSMC differentiation markers and eventually exacerbating TAD development. ROCK (Rho kinase) inhibitor Y-27632 reversed the protective role of LGMN depletion in vascular dissection. LGMN signaling may be a novel target for the prevention and treatment of TAD.

A Novel Approach to Minimising Acute Equine Endometritis That May Help to Prevent the Development of the Chronic State.

One of the most commonly encountered challenges in equine breeding is endometritis, which can be difficult to resolve and causes considerable economic losses to the industry. It is a multifactorial condition, developing as an exaggerated form of the normal physiological response to breeding. Seminal plasma proteins, spermatozoa, bacteria and debris initiate an inflammatory response; the resulting fluid and neutrophils are then cleared from the uterus along with the debris. However, in some mares, the response is prolonged or exaggerated, with much fluid formation and neutrophil infiltration leading to acute endometritis. A bacterial cause has been implicated, although in some cases no pathogenic organisms can be isolated on culture. It has been postulated that any one of a variety of bacteria could be involved, or dysbiosis of the uterine microbiome could be responsible. Repeated episodes of acute endometritis may lead to the pathology associated with chronic endometritis, with mucociliary dysfunction, vascular degeneration and plasma cell infiltration. This review examines the information that is currently available about equine endometritis, particularly about the role of the inseminate in the uterus, and its current treatment. There are some promising lines of research into treatment or prevention that may help to resolve the issue.

The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis

Tumor angiogenesis is the center of tumor growth and metastasis, and it increases the supply of nutrients and oxygen to tumors, thereby supporting tumor growth and progression. Vascular endothelial growth factor (VEGF) is a stimulator of angiogenesis and also plays a key role in the process of angiogenesis. Overexpression of VEGF is associated with tumor angiogenesis, promotion of tumor growth and reduced survival rate of patients. Notch signaling is a key pathway that regulates the response to angiogenesis stimulation during embryonic vascular development and postnatal angiogenesis, and is involved in multiple steps of angiogenesis. Dll4 is the only Notch ligand mainly expressed in endothelial cells, which can propagate by activating Notch signal and regulate tumor angiogenesis. Notch signaling pathway and VEGF pathway have both independent and synergistic effects, and Notch is necessary for VEGF-mediated vascular remodeling. The pathways cross each other and jointly regulate tumor angiogenesis. This review reviews the relationship between dLL4-notch-VEGFR2 signaling pathway composition, transduction and regulation and tumor angiogenesis. Combined blocking of DLL4-notch-VEGFR2 signaling pathway can significantly reduce vascular perfusion, resulting in vascular degeneration and reduced tumor survival. It can destroy the vascular system and survival ability of the primary tumor more than blocking alone, thus providing a new idea for the treatment of tumor, which is of great significance for the future anti-angiogenesis therapy.

Emerging roles of circular RNAs in retinal diseases.

Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina. Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration. In this review, we explore a relatively new field of research involving circular RNAs, whose potential roles as biomarkers and mediators of retinal disease pathogenesis have only just emerged. While knowledge of circular RNAs function is limited given its novelty, current evidence has highlighted their roles as modulators of microRNAs, regulators of gene transcription, and biomarkers of disease development and progression. Here, we summarize how circular RNAs may be implicated in the pathogenesis of common retinal diseases including diabetic retinopathy, glaucoma, proliferative vitreoretinopathy, and age-related macular degeneration. Further, we explore the potential of circular RNAs as novel biomarkers and therapeutic targets for the diagnosis and treatment of retinal diseases.