Development Of Vascular System Research Articles

Mechanism of CXCL8 regulation of methionine metabolism to promote angiogenesis in gliomas

BackgroundGliomas are the most common malignant brain tumors characterized by angiogenesis and invasive growth. A detailed understanding of its molecular characteristics could provide potential therapeutic targets. In the present study, we sought to explore the key gene CXCL8 in methionine metabolism in gliomas and its potential role in angiogenesis.MethodsU251 glioma cells were divided into control and methionine-restriction tolerant (constructed with 1/4 of the standard level of methionine in the culture medium) groups for transcriptome and metabolome analysis. To confirm the functions and mechanism of CXCL8 in glioma, heat map, volcano map, Go enrichment, gene set enrichment analysis (GSEA), protein–protein interaction network analysis, RT-PCR, western blotting assays, chicken embryo chorioallantoic membrane (CAM) test, chicken embryo yolk sac membrane (YSM) test and transplantation tumor nude mice model were performed. The TCGA database, CGGA database and clinical tissue samples were used to analyze CXCL8’s significance on prognosis for patients with glioma.ResultsCXCL8 expression was significantly up-regulated in methionine-restricted tolerance cells, it also activated vascular system development and triggered angiogenesis. CXCL8 expression is negatively correlated with survival prognosis in gliomas.ConclusionsGlioma cells promote angiogenesis in methionine-restricted environments through the activation of CXCL8, compensating for nutrient deprivation, and possibly contributing to the failure of antiangiogenic therapy.

Gene therapy with lipid nanoparticles for Fabry disease: Leveraging E-selectin for targeted delivery to endothelial cells

Fabry disease (FD) is caused by deficiency of activity of the lysosomal enzyme α-Galactosidase A (α-Gal A) throughout the organism, and vascular dysfunction represents the main pathological event causing life-threatening complications. Therefore, endothelial cells (ECs) are currently receiving attention as potential targets for the development of innovative therapies for FD, including gene therapy. However, the difficulty of transfecting ECs poses a major challenge to the development of vascular endothelial-targeted nucleic acid delivery systems. In the present study, we have developed lipid nanoparticles (LNPs) coupled with antibodies against the E-selectin to deliver pDNA encoding α-Gal A specifically to activated ECs, which express E-selectin. Coupled LNPs showed significantly higher cell association than uncoupled LNPs in activated Human Umbilical Vein Endothelial Cells (HUVECs) and in a cellular model of FD (Immortalized Fabry Endothelial Cell Line-1 (IMFE-1)), and this was translated into a higher transfection efficacy. Additionally, in IMFE-1 cells, antibody-coupled LNPs increased α-Gal A activity to levels 6.5-fold higher than untreated cells. In conclusion, E-selectin-targeted LNPs encapsulating pDNA showed enhanced transfection efficacy in activated ECs and the ability to increase α-Gal A activity in an FD cellular model, opening the door to a new therapeutic strategy in the treatment of FD.

Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema.

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2/TIE1 pathway in lymphatic function.

Comparison of two graft procedures in a bilateral sinus lift by MRI and histomorphometric analysis: a case report

Magnetic resonance imaging (MRI) was shown to be a viable method for graft healing evaluation. Platelet-rich fibrin (PRF) was found to speed up bone graft healing process. Sinus lift surgery outcomes after healing period are usually performed with computerized tomography that is not capable to describe graft vascularization and exposes patient to ionizing radiation. The objective of this study is to propose contrast-enhanced magnetic resonance imaging (CE-MRI) as a promising method for the in vivo assessment of sinus lift grafting procedures. A bilateral sinus augmentation surgery was performed. Left sinus was grafted only with bovine deproteinized bone mixed in a 1:1 ratio with autologous bone, in the right sinus, the same biomaterials with the addition of platelet-rich fibrin (PRF) were applied. CE-MRI was performed to evaluate angiogenesis before surgery and at 11, 25, 53, and 104 days after surgery. At 6 months (T0) and after 10 years (T1), before dental implants insertion, bone biopsies were performed and analysed quantitatively. Left sinus graft showed a centripetal pattern of angiogenesis, with the central region remaining unvascularized at 104 days post-surgery. Right side showed a wider and homogeneous vascularization from 25 days after surgery. At T0 new bone formation was only peripheral in the left sinus, whereas it developed both peripherally and through biomaterial in the right sinus. At T1 particles of biomaterial were still present in left sinus, while in right sinus they were not. CE-MRI offers quantitative parameters to evaluate vascularization of biomaterials. The addition of PRF promotes an early development of a widespread vascular system.

Vascular development, remodeling and maturation.

The development of the vascular system is crucial in supporting the growth and health of all other organs in the body, and vascular system dysfunction is the major cause of human morbidity and mortality. This chapter discusses three successive processes that govern vascular system development, starting with the differentiation of the primitive vascular system in early embryonic development, followed by its remodeling into a functional circulatory system composed of arteries and veins, and its final maturation and acquisition of an organ specific semi-permeable barrier that controls nutrient uptake into tissues and hence controls organ physiology. Along these steps, endothelial cells forming the inner lining of all blood vessels acquire extensive heterogeneity in terms of gene expression patterns and function, that we are only beginning to understand. These advances contribute to overall knowledge of vascular biology and are predicted to unlock the unprecedented therapeutic potential of the endothelium as an avenue for treatment of diseases associated with dysfunctional vasculature.

Evidence for poplar PtaPLATZ18 in the regulation of plant growth and vascular tissues development.

Plant A/T-rich protein and zinc-binding protein (PLATZ) are plant-specific transcription factors playing a role in plant development and stress response. To assess the role of PLATZs in vascular system development and wood formation in poplar, a functional study for PtaPLATZ18, whose expression was associated with the xylem, was carried out. Poplar dominant repressor lines for PtaPLATZ18 were produced by overexpressing a PtaPLATZ18-SRDX fusion. The phenotype of three independent transgenic lines was evaluated at morphological, biochemical, and molecular levels and compared to the wild type. The PtaPLATZ18-SRDX lines showed increased plant height resulting from higher internode length. Besides, a higher secondary xylem thickness was also evidenced in these dominant repression lines as compared to the wild type suggesting an activation of cambial activity. A higher amount of lignin was evidenced within wood tissue as compared to the wild type, indicating an alteration in cell wall composition within xylem cell types. This latter phenotype was linked to an increased expression of genes involved in lignin biosynthesis and polymerization. The phenotype observed in the PtaPLATZ18-SRDX lines argues that this transcription factor targets key regulators of plant growth and vascular tissues development.

Generation of heart and vascular system in rodents by blastocyst complementation

Generating organs from stem cells through blastocyst complementation is a promising approach to meet the clinical need for transplants. In order to generate rejection-free organs, complementation of both parenchymal and vascular cells must be achieved, as endothelial cells play a key role in graft rejection. Here, we used a lineage-specific cell ablation system to produce mouse embryos unable to form both the cardiac and vascular systems. By mouse intraspecies blastocyst complementation, we rescued heart and vascular system development separately and in combination, obtaining complemented hearts with cardiomyocytes and endothelial cells of exogenous origin. Complemented chimeras were viable and reached adult stage, showing normal cardiac function and no signs of histopathological defects in the heart. Furthermore, we implemented the cell ablation system for rat-to-mouse blastocyst complementation, obtaining xenogeneic hearts whose cardiomyocytes were completely of rat origin. These results represent an advance in the experimentation towards the invivo generation of transplantable organs.

Optoacoustic angiography for noninvasive monitoring of experimental tumor angiogenesis

The paper demonstrates the results of a study of experimental SN-12C xenograft vascular network formation using optoacoustic microscopy. A sevenfold increase in vascularity during tumor growth from days 7 to 121 was shown. The possibility of monitoring the development of individual vessels inside the tumor node has been demonstrated. The data obtained are important for understanding the mechanisms of development of the tumor vascular system and may be useful in testing antiangiogenic therapeutic agents.

Placental Growth Factor and Pregnancy-Associated Plasma Protein-A as Potential Early Predictors of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and one of the main causes of adverse pregnancy outcomes. An early diagnosis of GDM is of fundamental importance in clinical practice. However, the major professional organizations recommend universal screening for GDM, using a 75 g oral glucose tolerance test at 24-28 weeks of gestation. A selective screening at an early stage of pregnancy is recommended only if there are maternal risk factors for diabetes. As a result, the GDM diagnosis is often delayed and established after the appearance of complications. The manifestation of GDM is directly related to insulin resistance, which is closely associated with endothelial dysfunction. The placenta, the placental peptides and hormones play a pivotal role in the manifestation and progression of insulin resistance during pregnancy. Recently, the placental growth factor (PlGF) and plasma-associated protein-A (PAPP-A), have been shown to significantly affect both insulin sensitivity and endothelial function. The principal function of PAPP-A appears to be the cleavage of circulating insulin-like growth factor binding protein-4 while PlGF has been shown to play a central role in the development and maturation of the placental vascular system and circulation. On one hand, these factors are widely used as early predictors (11-13 weeks of gestation) of complications during pregnancy, such as preeclampsia and fetal aneuploidies, in most countries. On the other hand, there is increasing evidence for their predictive role in the development of carbohydrate disorders, but some studies are rather controversial. Therefore, this review aims to summarize the available literature about the potential of serum levels of PlGF and PAPP-A as early predictors in the diagnosis of GDM.

Andrographolide suppresses hypoxia-induced embryonic hyaloid vascular system development through HIF-1a/VEGFR2 signaling pathway.

Ocular abnormalities and the development of retinal vasculature may cause postnatal retinopathy. In the past decade, tremendous progress has been made in identifying the mechanisms that regulate retina vasculature. However, the means of regulating embryonic hyaloid vasculature development is largely unknown. This study aims to determine whether and how andrographolide regulates embryonic hyaloid vasculature development. Murine embryonic retinas were used in this study. Whole mount isolectin B4 (IB4) staining, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and immunofluorescence staining (IF) were performed to determine whether andrographolide is critical for embryonic hyaloid vasculature development. BrdU incorporation assay, Boyden chamber migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay were performed to evaluate whether andrographolide regulates the proliferation and migration of vascular endothelial cells. Molecular docking simulation and Co-immunoprecipitation assay were used to observe protein interaction. Hypoxia conditions exist in murine embryonic retinas. Hypoxia induces HIF-1a expression; high-expressed HIF-1a interacts with VEGFR2, resulting in the activation of the VEGF signaling pathway. Andrographolide suppresses hypoxia-induced HIF-1a expression and, at least in part, interrupts the interaction between HIF-1a and VEGFR2, causing inhibiting endothelial proliferation and migration, eventually inhibiting embryonic hyaloid vasculature development. Our data demonstrated that andrographolide plays a critical role in regulating embryonic hyaloid vasculature development.

Molecular mechanisms of vascular tissue patterning in Arabidopsis thaliana L. roots.

A vascular system in plants is a product of aromorphosis that enabled them to colonize land because it delivers water, mineral and organic compounds to plant organs and provides effective communications between organs and mechanical support. Vascular system development is a common object of fundamental research in plant development biology. In the model plant Arabidopsis thaliana, early stages of vascular tissue formation in the root are a bright example of the self-organization of a bisymmetric (having two planes of symmetry) pattern of hormone distribution, which determines vascular cell fates. In the root, vascular tissue development comprises four stages: (1) specification of progenitor cells for the provascular meristem in early embryonic stages, (2) the growth and patterning of the embryo provascular meristem, (3) postembryonic maintenance of the cell identity in the vascular tissue initials within the root apical meristem, and (4) differentiation of their descendants. Although the anatomical details of A. thaliana root vasculature development have long been known and described in detail, our knowledge of the underlying molecular and genetic mechanisms remains limited. In recent years, several important advances have been made, shedding light on the regulation of the earliest events in provascular cells specification. In this review, we summarize the latest data on the molecular and genetic mechanisms of vascular tissue patterning in A. thaliana root. The first part of the review describes the root vasculature ontogeny, and the second reconstructs the sequence of regulatory events that underlie this histogenesis and determine the development of the progenitors of the vascular initials in the embryo and organization of vascular initials in the seedling root.

Oxamyl exerts developmental toxic effects in zebrafish by disrupting the mitochondrial electron transport chain and modulating PI3K/Akt and p38 Mapk signaling

Oxamyl, a carbamate insecticide, is mainly used to control nematodes in the agricultural field. Although oxamyl is a widely used insecticide that is associated with ecological concerns, limited studies have examined the toxic effects of oxamyl on the developmental stage and the underlying mechanisms. In this study, the developmental toxicity of oxamyl was demonstrated using zebrafish, which is a representative model as it is associated with rapid embryogenesis and a toxic response similar to that of other vertebrates. The morphological alteration of zebrafish larvae was analyzed to confirm the sub-lethal toxicity of oxamyl. Analysis of transgenic zebrafish (olig2:dsRED and flk1:eGFP line) and mRNA levels of genes associated with individual organ development revealed that oxamyl exerted toxic effects on the development of neuron, notochord, and vascular system. Next, the adverse effect of oxamyl on the mitochondrial electron transport chain was examined. Treatment with oxamyl altered the PI3K/Akt signaling and p38 Mapk signaling pathways in zebrafish. Thus, this study elucidated the mechanisms underlying the developmental toxicity of oxamyl and provided information on the parameters to assess the developmental toxicity of other environmental contaminants.

A Transwell-Based Vascularized Model to Investigate the Effect of Interstitial Flow on Vasculogenesis.

Interstitial flow plays a significant role in vascular system development, mainly including angiogenesis and vasculogenesis. However, compared to angiogenesis, the effect of interstitial flow on vasculogenesis is less explored. Current in vitro models for investigating the effect of interstitial flow on vasculogenesis heavily rely on microfluidic chips, which require microfluidic expertise and facilities, and may not be accessible to biological labs. Here, we proposed a facile approach to building perfusable vascular networks through the self-assembly of endothelial cells in a modified transwell format and investigated the effect of interstitial flow on vasculogenesis. We found that the effect of interstitial flow on vasculogenesis was closely related to the existence of VEGF and fibroblasts in the developed model: (1) In the presence of fibroblasts, interstitial flow (within the range of 0.1-0.6 μm/s) facilitated the perfusability of the engineered vasculatures. Additional VEGF in the culture medium further worked synergically with interstitial flow to develop longer, wider, denser, and more perfusable vasculatures than static counterparts; (2) In the absence of fibroblasts, vasculatures underwent severe regression within 7 days under static conditions. However, interstitial flow greatly inhibited vessel regression and enhanced vascular perfusability and morphogenesis without the need for additional VEGF. These results revealed that the effect of interstitial flow might vary depending on the existence of VEGF and fibroblasts, and would provide some guidelines for constructing in vitro self-assembled vasculatures. The established transwell-based vascularized model provides a simple method to build perfusable vasculatures and could also be utilized for creating functional tissues in regenerative medicine.

Impairment of sugar transport in the vascular system acts on nitrogen remobilization and nitrogen use efficiency in Arabidopsis.

Carbon (C) and nitrogen (N) metabolisms have long been known to be coupled, and this is required for adjusting nitrogen use efficiency (NUE). Despite this intricate relationship, it is still unclear how deregulation of sugar transport impacts N allocation. Here, we investigated in Arabidopsis the consequences of the simultaneous downregulation of the genes coding for the sugar transporters SWEET11, SWEET12, SWEET16, and SWEET17 on various anatomical and physiological traits ranging from the stem's vascular system development to plant biomass production, seed yield, and N remobilization and use efficiency. Our results show that intracellular sugar exchanges mediated by SWEET16 and SWEET17 proteins specifically impact vascular development but do not play a significant role in the distribution of N. Most importantly, we showed that the double mutant swt11 swt12, which has an impacted vascular development, displays an improved NUE and nitrogen remobilization to the seeds. In addition, a significant negative correlation between sugar and amino acids contents and the inflorescence stem radial growth exists, highlighting the complex interaction between the maintenance of C/N homeostasis and the inflorescence stem development. Our results thus deepen the link between sugar transport, C/N allocation, and vascular system development.

Role of miRNAs in vascular development.

The development of the vertebrate vascular system is an extremely important and complex process. The circulatory system is the first organ system to develop during embryogenesis. The development of the vasculature into highly branched canals must occur clearly in many places in order to supply oxygen and nutrients to the rapidly developing embryo. This process is mediated by a coordinated response of vascular endothelial and parietal cells to heterogeneous angiogenic signals provided by tissues and organs. MicroRNAs regulate gene expression at the transcriptional and post-transcriptional levels and participate in many important physiological and pathological processes. MicroRNAs mainly play an important role in the developmental regulation of vascular smooth muscle cells and vascular endothelial cells. This article summarizes the research progress of microRNAs in vascular development in recent years, focusing on the regulatory mechanism of miR-126 and miR-17/92 families in vascular endothelial cells, as well as the miR-143/145 family, miR-21 in vascular smooth muscle cell's regulation. The research prospects of the role of microRNAs in vascular development are also presented in this article.

Integrating network pharmacology, transcriptomics, and molecular simulation to reveal the mechanism of tert-butylhydroquinone for treating diabetic retinopathy

Diabetic retinopathy (DR), a common microvascular complication of diabetes mellitus, is a significant cause of blindness. As one of the crucial factors in the pathogenesis of DR, oxidative stress provides new insights for the treatment of DR. Tert-butylhydroquinone (TBHQ), an efficient phenolic antioxidant, has been proved to inhibit diabetic retina injury. However, the mechanism of TBHQ for DR treatment is still unclear. The present study was designed to investigate the potential mechanism of TBHQ for treating DR. Firstly, the potential targets of TBHQ and DR were selected to construct protein-protein interaction network, which was applied to illustrate the potential mechanism of TBHQ against DR. Combined with transcriptomics and molecular simulation, the potential mechanisms were systematically verified. The results showed that TBHQ inhibited retinal microvascular injury by regulating oxidative stress, inflammation, cell proliferation-death regulation, and vascular system development. The mechanisms of these activities were associated with hypoxia-inducible factor-1 (HIF-1), nuclear factor-erythroid 2 related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), forkhead box O (FoxO), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and rhoptry-associated protein1 (Rap1) signaling pathways and their related targets nitric oxide synthase 3 (NOS3), mitogen-activated protein kinase 8 (MAPK8), prostaglandin-endoperoxide synthase 2 (PTGS2), and heme oxygenase 1 (HMOX1). In conclusion, a systematic perspective for the mechanism of TBHQ against DR was revealed by present study which lays a foundation for the application of TBHQ in treating DR.

Autotaxin Activity in Chronic Subdural Hematoma: A Prospective Clinical Study.

Autotaxin (ATX) is the ectoenzyme producing the bulk of lysophosphatidic acid (LPA) in circulation. ATX and LPA-mediated signaling (the ATX-LPA axis) play critical roles in the vascular and nervous system development. In adults, this axis contributes to diverse processes, including coagulation, inflammation, fibroproliferation and angiogenesis under physiological and/or pathophysiological conditions. Given evidence implicating several of these processes in chronic subdural hematoma (CSDH) pathogenesis and development, we assessed ATX activity in CSDH patients. Twenty-eight patients were recruited. Blood and hematoma fluid were collected. Enzymatic assays were used to establish serum and hematoma ATX activity. Enzyme-linked immunosorbent assays were used to establish hematoma beta trace (BT) levels, a cerebrospinal fluid (CSF) marker, in a hematoma. ATX activity was nearly three folds higher in hematoma compared to serum (P < 0.001). There was no significant correlation between BT levels and ATX activity in a hematoma. The present results show, for the first time, that ATX is catalytically active in the hematoma fluid of CSDH patients. Moreover, our findings of significantly elevated ATX activity in hematoma compared to serum, implicate the ATX-LPA axis in CSDH pathophysiology. The CSF origin of ATX could not be inferred with the present results. Additional research is warranted to establish the significance of the ATX-LPA axis in CSDH and its potential as a biomarker and/or therapeutic target.

Omics approaches to discover pathophysiological pathways contributing to human pain.

Omics approaches to discover pathophysiological pathways contributing to human pain.

Preclusive Strategies of Obesity to Lead a Healthy Life - A Review

Obesity is not an ailment, because it is one of the intricate contributing causes of a number of Non-Communicable Diseases (NCD), such as heart disease, diabetes, osteoarthritis, cancer, kidney stones, inflammation, backache, etc., that are prevalent in people all over the world. A sedentary lifestyle raises body fat accumulation, which causes weight gain, which is a primary consequence of metabolic disorders. The major goal of this brief review was to identify and be aware of the prevalence and preclusive strategies to overcome obesity using reputed studies. As per the World Health Organization (WHO), since 1980, the incidence of overweight in the community has roughly doubled. According to the International Obesity Task Force (IOTF), 312 million individuals nationally and internationally minimum of 1.1 billion are obese. According to the Institute of Medicine (IOM) Committee of the United States of America, a complete plan to increase weight control in key places is established when the objectives, policies, and implementation activities are incorporated. The first and most amazing requirement of life is physical activity intervention, which improves human health through started trying techniques, professionally studied workouts, and conditioning that eventually lowers fatality and also considerably fosters the development of muscle contraction, muscle mass, vascular system, and calcified bones. The review concludes by restating the importance of maintaining a healthy weight and a proper BMI control regimen. Regular physical activity helps to strengthen internal organs and supports the secretary process. Moderate-intensity physical activity has been used to manage weight for a long time.

Role of Neuropilin-2-mediated signaling axis in cancer progression and therapy resistance.

Neuropilins (NRPs) are transmembrane proteins involved in vascular and nervous system development by regulating angiogenesis and axon guidance cues. Several published reports have established their role in tumorigenesis. NRPs are detectable in tumor cells of several cancer types and participate in cancer progression. NRP2 is also expressed in endothelial and immune cells in the tumor microenvironment and promotes functions such as lymphangiogenesis and immune suppression important for cancer progression. In this review, we have taken a comprehensive approach to discussing various aspects of NRP2-signaling in cancer, including its regulation, functional significance in cancer progression, and how we could utilize our current knowledge to advance the studies and target NRP2 to develop effective cancer therapies.