Regulation Of Vascular Development Research Articles

GGT5 as a promising prognostic biomarker and its effects on tumor cell progression in gastric cancer.

Gastric cancer (GC) is a gastric malignant tumor with over 1 million new cases globally each year. There are many diagnostic methods for GC, but due to the hidden early symptoms of GC, early GC is easy to be missed and misdiagnosed, which affects the follow-up treatment of patients. The early and accurate diagnosis of GC is of great significance for the treatment and survival of GC patients. Our laboratory study found that gamma-glutamyl transferase (GGT) was highly expressed in GC patients, but the mechanism of GGT family genes in the occurrence and development of GC remained to be further studied. Therefore, this study aimed to explore the mechanism of GGT family functional gene GGT5 regulating the proliferation and migration of GC cells, and provide a possible new biomarker for the early diagnosis of GC. The value of serum GGT in GC patients was first statistically analyzed. Then, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to analyze the mRNA expression of GGT5 in GC, and its clinical relationship and function. Furthermore, expression of GGT5 was reduced by lentivirus RNA interference and verified by polymerase chain reaction (PCR), Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to detect cell proliferation after GGT5 knockdown. Scratch and Transwell assays were applied to observe cell migration after knockdown of GGT5. Finally, Western blot assays were observed to demonstrate PI3K/AKT-MAPK and MMPs expression levels after knockdown of GGT5. Serum GGT was expressed at a high level in GC patients. GGT5 was highly expressed in GC tissues, and was associated with poor prognosis and clinical stage of GC. GGT5 might be involved in the regulation of vascular development and angiogenesis, as well as in the mechanisms of cell motility and migration, and it was positively correlated with the PI3K/AKT pathway. The proliferation and migration capacity of GC cells was dampened by downregulation of GGT5. GGT5 mediated proliferation and migration of GC cells by directly targeting PI3K/AKT-MAPK-MMPs pathways. Low expression of GGT5 reduced proliferation and migration in GC cells by modulating the PI3K/AKT-MAPK-MMPs pathway, and GGT5 might be a new target for GC.

Radiographic evaluation of the healing process of alveolar abscess through regulation of VEGF and angiogenesis

Objectives: This review article aims to explain how the regulation of vascular endothelial growth factor (VEGF) and angiogenesis on alveolar abscess healing process evaluation using radiograph. Review: The databases used in this review are Google Scholar, PubMed, and Science Direct. A total of 1280 search results appeared based on keywords. The search results were selected by title and abstract according to their relevance to the review topic. A total of 24 literatures were reviewed. The alveolar bone destruction is one of the signs of an inflammatory lesion in the alveolar bone. Bone damage that occurs in cases of the abscess will reduce the absorption of x-rays thereby giving a radiolucent appearance on radiographic examination. A radiographic examination is a supporting examination that can be used to develop the healing process. The processes of angiogenesis and osteogenesis of bone homeostasis will complement each other for the bone healing process, while VEGF is a growth factor that can increase the expression of BMPs and osteoblast differentiation so that the bone healing process can take place properly. Conclusion: VEGF plays a significant role in both bone healing and regulation of vascular development and angiogenesis. However, excessive VEGF can also be harmful to the process of bone repair because it can stimulate the recruitment of osteoclasts. Therefore, VEGF regulation has an important role in apical abscess healing, and radiographic images that are quantitatively analyzed can be used to quantify this healing process.

Three-dimensional reconstruction and multiomics analysis reveal a unique pattern of embryogenesis in Ginkgo biloba.

Ginkgo (Ginkgo biloba L.) is one of the earliest extant species in seed plant phylogeny. Embryo development patterns can provide fundamental evidence for the origin, evolution, and adaptation of seeds. However, the architectural and morphological dynamics during embryogenesis in G. biloba remain elusive. Herein, we obtained over 2,200 visual slices from 3 stages of embryo development using micro-computed tomography imaging with improved staining methods. Based on 3-dimensional (3D) spatiotemporal pattern analysis, we found that a shoot apical meristem with 7 highly differentiated leaf primordia, including apical and axillary leaf buds, is present in mature Ginkgo embryos. 3D rendering from the front, top, and side views showed 2 separate transport systems of tracheids located in the hypocotyl and cotyledon, representing a unique pattern of embryogenesis. Furthermore, the morphological dynamic analysis of secretory cavities indicated their strong association with cotyledons during development. In addition, we identified genes GbLBD25a (lateral organ boundaries domain 25a), GbCESA2a (cellulose synthase 2a), GbMYB74c (myeloblastosis 74c), GbPIN2 (PIN-FORMED 2) associated with vascular development regulation, and GbWRKY1 (WRKYGOK 1), GbbHLH12a (basic helix-loop-helix 12a), and GbJAZ4 (jasmonate zim-domain 4) potentially involved in the formation of secretory cavities. Moreover, we found that flavonoid accumulation in mature embryos could enhance postgerminative growth and seedling establishment in harsh environments. Our 3D spatial reconstruction technique combined with multiomics analysis opens avenues for investigating developmental architecture and molecular mechanisms during embryogenesis and lays the foundation for evolutionary studies of embryo development and maturation.

MicroRNA-299-3p inhibits cell proliferation, motility, invasion and angiogenesis via VEGFA in upper tract urothelial carcinoma.

Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different features between Eastern and Western countries. Vascular endothelial growth factor-A (VEGFA) was originally identified as a secreted signaling protein and regulator of vascular development and cancer progression. In this study, we aimed to elucidate the molecular mechanisms underlying the regulation of VEGFA by microRNA in UTUC. VEGFA expression was evaluated by immunohistochemistry in 140 human UTUC tissue samples. Next, we assessed the regulatory relationship between VEGFA and miR-299-3p by real-time PCR, western blotting, ELISA and dual-luciferase reporter assays using two UTUC cell lines. The role of miR-299-3p/VEGFA in cell proliferation, motility, invasion, and tube formation was analyzed in vitro. High VEGFA expression was significantly associated with tumor stage, grade, distant metastasis and cancer-related death and correlated with poor progression-free and cancer-specific survival. VEGFA knockdown repressed proliferation, migration, invasion and angiogenesis in UTUC cell lines. miR-299-3p significantly reduced VEGFA protein expression and miR-299-3p overexpression inhibited VEGFA mRNA and protein expression by directly targeting its 3'-UTR. Functional studies indicated that VEGFA overexpression reversed the miR-299-3p-mediated suppression of tumor cell proliferation, migration, invasion and angiogenesis. In addition, miR-299-3p/VEGFA suppressed cellular functions in UTUC by modulating the expression of P18 and cyclin E2. Our findings suggest that miR-299-3p possibly suppresses UTUC cell proliferation, motility, invasion and angiogenesis via VEGFA. VEGFA may act as a prognostic predictor, and both VEGFA and miR-299-3p could be potential therapeutic targets for UTUC.

DDEL-06. MICROGLIA REPAIR THE DISRUPTED BLOOD-BRAIN BARRIER FOLLOWING LOW-INTENSITY PULSED ULTRASOUND THROUGH P2RY12 SIGNALING

Abstract In a phase I clinical trial for patients with recurrent glioblastoma, we used an implantable ultrasound device for low-intensity pulsed ultrasound and microbubbles (LIPU/MB) to open the blood-brain barrier (BBB). This strategy increased parenchymal drug concentrations by 3.7- to 5.9-fold. Magnetic resonance imaging analysis with gadolinium injections at different timepoints post-sonication revealed that the BBB integrity began to restore within an hour post-sonication. To investigate the effect of LIPU/MB, we biopsied sonicated and non-sonicated peritumoral brain regions 45 minutes post-sonication before tumor resection in 7 patients. Single-cell RNA sequencing analysis revealed that sonicated microglia clustered separately and had enrichment of gene ontology terms related to the positive regulation of cell adhesion (p < 2x10-6), wound healing (p < 3x10-5), and regulation of vascular development and angiogenesis (p < 4x10-5). Upregulated genes included IL1B (log2fold-change 2.9, p < 1x10-140), PLAUR (log2fold-change 1.9, p < 2x10-177), and VEGFA (log2fold-change 1.8, p < 1x10-125). We also evaluated the spatial distribution of microglia in sonicated and non-sonicated samples by multiplex immunofluorescence. Analysis of 20 vessels per sample demonstrated that sonicated microglia accumulated around blood vessels, averaging at 14 μm from CD31+ cells, compared to 45 μm in non-sonicated biopsies (p < 0.01). Based on previous reports of P2RY12-dependent microglial migration and repair of the BBB, we evaluated the effect of P2RY12 inhibition with clopidogrel on BBB repair post-sonication in mice. Permeability assay with fluorescein revealed that the BBB was 80% (p < 0.001) and 50% (p < 0.05) more permeable at 10 and 45 minutes post-sonication in clopidogrel-treated mice, respectively. This work provides human data supporting the role of microglia in the repair of the BBB, previously described in animals, and provides preclinical and clinical evidence for the role of these cells in the rapid restoration of vascular integrity post-LIPU/MB in humans.

High temperature inhibits vascular development via the PIF4-miR166-HB15 module in Arabidopsis

The plant vascular system is an elaborate network of conducting and supporting tissues that extends throughout the plant body, and its structure and function must be orchestrated with different environmental conditions. Under high temperature, plants display thin and lodging stems that may lead to decreased yield and quality of crops. However, the molecular mechanism underlying high-temperature-mediated regulation of vascular development is not known. Here, we show that Arabidopsis plants overexpressing the basic-helix-loop-helix (bHLH) transcription factor PHYTOCHROME INTERACTING FACTOR 4 (PIF4), a central regulator of high-temperature signaling, display fewer vascular bundles (VBs) and decreased secondary cell wall (SCW) thickening, mimicking the lodging inflorescence stems of high-temperature-grown wild-type plants. Rising temperature and elevated PIF4 expression reduced the expression of MIR166 and, concomitantly, elevated the expression of the downstream class III homeodomain leucine-zipper (HD-ZIP III) family gene HB15. Consistently, knockdown of miR166 and overexpression of HB15 led to inhibition of vascular development and SCW formation, whereas the hb15 mutant displayed the opposite phenotype in response to high temperature. Moreover, invitro and invivo assays verified that PIF4 binds to the promoters of several MIR166 genes and represses their expression. Our study establishes a direct functional link between PIF4 and the miR166-HB15 module in modulating vascular development and SCW thickening and consequently stem-lodging susceptibility at elevated temperatures.

Sucrose Signaling Contributes to the Maintenance of Vascular Cambium by Inhibiting Cell Differentiation.

Plants produce sugars by photosynthesis and use them for growth and development. Sugars are transported from source-to-sink organs via the phloem in the vasculature. It is well known that vascular development is precisely controlled by plant hormones and peptide hormones. However, the role of sugars in the regulation of vascular development is poorly understood. In this study, we examined the effects of sugars on vascular cell differentiation using a vascular cell induction system named 'Vascular Cell Induction Culture System Using Arabidopsis Leaves' (VISUAL). We found that sucrose has the strongest inhibitory effect on xylem differentiation, among several types of sugars. Transcriptome analysis revealed that sucrose suppresses xylem and phloem differentiation in cambial cells. Physiological and genetic analyses suggested that sucrose might function through the BRI1-EMS-SUPPRESSOR1 transcription factor, which is the central regulator of vascular cell differentiation. Conditional overexpression of cytosolic invertase led to a decrease in the number of cambium layers due to an imbalance between cell division and differentiation. Taken together, our results suggest that sucrose potentially acts as a signal that integrates environmental conditions with the developmental program.

PDGFRB upregulation contributes to retinal damages in the rat model of retinal ischemia-reperfusion

Retinal ischemic disease is a major type of retinal diseases causing vision loss. Identifying the molecular mechanisms mediating the retinal ischemia-reperfusion (RIR) is the key to targeted intervention. In this study, we performed RNA-seq analysis of the retinal tissues of a retinal ischemia-reperfusion model of Sprague-Dawley (SD) rats, followed by differential gene expression analysis, gene ontology (GO) enrichment analysis, and protein-protein interaction (PPI) analysis. After studying we found that: The major biological processes affected after RIR was the regulation of vascular development. PPI analysis unveiled a regulatory module in which Platelet Derived Growth Factor Receptor Beta (PDGFRB) was upregulated. In the RIR cell model of human retinal microvascular endothelial cells (HRCEC) induced by oxygen-glucose deprivation/reperfusion (OGD/R), silencing PDGFRB at least partially rescued the detrimental effect on cell proliferation and in vitro angiogenic ability. In the rat model of RIR, the administration of PDGFR inhibitor alleviated the damages in the retinal microvascular system. Besides, we further demonstrated the protective effect of procyanidin against RIR induced damages in both the cell and animal model by dampening the overexpression of PDGFRB. Together, our data indicate that the upregulation of PDGFRB contributes to RIR-induced damages in retinal microvascular system, which provides a targetable strategy for therapeutic intervention.

Molecular and Cellular Regulations in the Development of the Choroidal Circulation System.

Disorders in the development and regulation of blood vessels are involved in various ocular disorders, such as persistent hyperplastic primary vitreous, familial exudative vitreoretinopathy, and choroidal dystrophy. Thus, the appropriate regulation of vascular development is essential for healthy ocular functions. However, regulation of the developing choroidal circulation system has not been well studied compared with vascular regulation in the vitreous and the retina. The choroid is a vascular-rich and uniquely structured tissue supplying oxygen and nutrients to the retina, and hypoplasia and the degeneration of the choroid are involved in many ocular disorders. Therefore, understanding the developing choroidal circulation system expands our knowledge of ocular development and supports our understanding of ocular disorders. In this review, we examine studies on regulating the developing choroidal circulation system at the cellular and molecular levels and discuss the relevance to human diseases.

Mapping the dynamics of insulin-responsive pathways in the blood–brain barrier endothelium using time-series transcriptomics data

Critical functions of the blood–brain barrier (BBB), including cerebral blood flow, energy metabolism, and immunomodulation, are regulated by insulin signaling pathways. Therefore, endothelial insulin resistance could lead to BBB dysfunction, which is associated with neurodegenerative diseases such as Alzheimer’s disease (AD). The current study aims to map the dynamics of insulin-responsive pathways in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. RNA-Sequencing was performed on hCMEC/D3 monolayers with and without insulin treatment at various time points. The Short Time-series Expression Miner (STEM) method was used to identify gene clusters with distinct and representative expression patterns. Functional annotation and pathway analysis of genes from selected clusters were conducted using Webgestalt and Ingenuity Pathway Analysis (IPA) software. Quantitative expression differences of 16,570 genes between insulin-treated and control monolayers were determined at five-time points. The STEM software identified 12 significant clusters with 6880 genes that displayed distinct temporal patterns upon insulin exposure, and the clusters were further divided into three groups. Gene ontology (GO) enrichment analysis demonstrated that biological processes protecting BBB functions such as regulation of vascular development and actin cytoskeleton reorganization were upregulated after insulin treatment (Group 1 and 2). In contrast, GO pathways related to inflammation, such as response to interferon-gamma, were downregulated (Group 3). The IPA analyses further identified insulin-responsive cellular and molecular pathways that are associated with AD pathology. These findings unravel the dynamics of insulin action on the BBB endothelium and inform about downstream signaling cascades that are potentially disrupted due to brain insulin resistance prevalent in AD.

New insights into aging-associated characteristics of female subcutaneous adipose tissue through integrative analysis of multi-omics data

ABSTRACT Aging could be critical in limiting the application of subcutaneous adipose tissue (SAT) in tissue repair and reconstruction. However, no systematic study on the characteristics of SAT aging has been conducted. In this study, a scanning electronic microscope was used to detect the structural and compositional changes of SAT collected from nine females in three age groups. Multi-omics data of SAT from 37 females were obtained from Gene Expression Omnibus database, and 1860 genes, 56 miRNAs, and 332 methylated genes were identified as being differentially expressed during aging among non-obese females. Using Weighted Correlation Network Analysis (WGCNA), 1754 DEGs were defined as aging-associated genes for non-obese females, distributed among ten co-expression modules. Through Gene Ontology enrichment analysis and Gene Set enrichment analysis on those aging-associated DEGs, SAT aging was observed to be characterized by variations in immune and inflammatory states, mitochondria, lipid and carbohydrate metabolism, and regulation of vascular development. SUPV3L1, OGT, and ARPC1B were identified as conserved and core SAT-aging-related genes, as verified by RT-qPCR among 18 samples in different age groups. Multi-omics regulatory networks of core aging-associated biological processes of SAT were also constructed. Based on WGCNA, we performed differential co-expression analysis to unveil the differences in aging-related co-expression patterns between obese and non-obese females and determined that obesity could be an important accelerating factor in aging processes. Our work provides a landscape of SAT aging, which could be helpful for further research in fields such as repair and reconstruction as well as aging.

Microvascular cells: A special focus on heterogeneity of pericytes in diabetes associated complications.

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

Comparative proteomic analysis of differentially expressed proteins related to phloem and xylem development in rubber tree (Hevea brasiliensis)

The proteomic analysis of vascular tissues in rubber tree reveals differentially expressed proteins related to laticifer differentiation in mature phloem and secondary cell wall formation in mature xylem for latex/wood-yield improvement. Rubber tree (Hevea brasiliensis) is a latex-producing plant that has worldwide economic importance for the rubber and wood industries. Natural rubber latex is produced from laticiferous vessels (laticifers) located in the secondary phloem tissue of rubber trees. Improving latex production from rubber tree clones by studying the molecular genetics of vascular development has received much attention, but less information has been obtained from proteomic approaches. This study performed a comparative proteomic analysis of the vascular tissues in high latex-yield and high wood-yield rubber tree clones. One primary vascular tissue (newly developed stem) and two secondary vascular tissues (mature phloem/laticifers and mature xylem/wood) were investigated by qualitative/quantitative proteomic analysis using GeLC-MS/MS. The differentially expressed proteins (DEPs) in the specific vascular tissues were analyzed, and the protein functions in the biological processes related to vascular development and to the specific characteristics of each clone were clarified. The predicted protein–protein interaction network and GO annotation revealed DEPs related to photosynthesis, carbohydrate metabolism, energy production and jasmonic acid-responsive proteins involved in positive regulation of laticifer differentiation in mature phloem of the high latex-yield clone, while DEPs related to cell cytoskeleton maintenance, secondary cell wall components and auxin-, brassinosteroid-, abscisic acid-responsive proteins involved in xylem differentiation were abundant in mature xylem of the high wood-yield clone. This is the first report to demonstrate the correlation and functions of DEPs in phloem/laticifers and xylem/wood differentiation in rubber trees. The regulation of vascular development could be useful in improvement of latex and wood yields from rubber trees.

Bioinformatic Analysis of Gene Variants from Gastroschisis Recurrence Identifies Multiple Novel Pathogenetic Pathways: Implication for the Closure of the Ventral Body Wall.

We investigated whether likely pathogenic variants co-segregating with gastroschisis through a family-based approach using bioinformatic analyses were implicated in body wall closure. Gene Ontology (GO)/Panther functional enrichment and protein-protein interaction analysis by String identified several biological networks of highly connected genes in UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, AOX1, NOTCH1, HIST1H2BB, RPS3, THBS1, ADCY9, and FGFR4. SVS–PhoRank identified a dominant model in OR10G4 (also as heterozygous de novo), ITIH3, PLEKHG4B, SLC9A3, ITGA2, AOX1, and ALPP, including a recessive model in UGT1A7, UGT1A6, PER2, PTPRD, and UGT1A3. A heterozygous compound model was observed in CDYL, KDM5A, RASGRP1, MYBPC2, PDE4DIP, F5, OBSCN, and UGT1A. These genes were implicated in pathogenetic pathways involving the following GO related categories: xenobiotic, regulation of metabolic process, regulation of cell adhesion, regulation of gene expression, inflammatory response, regulation of vascular development, keratinization, left-right symmetry, epigenetic, ubiquitination, and regulation of protein synthesis. Multiple background modifiers interacting with disease-relevant pathways may regulate gastroschisis susceptibility. Based in our findings and considering the plausibility of the biological pattern of mechanisms and gene network modeling, we suggest that the gastroschisis developmental process may be the consequence of several well-orchestrated biological and molecular mechanisms which could be interacting with gastroschisis predispositions within the first ten weeks of development.

Tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis

Angiogenesis requires co-ordination of multiple signalling inputs to regulate the behaviour of endothelial cells (ECs) as they form vascular networks. Vascular endothelial growth factor (VEGF) is essential for angiogenesis and induces downstream signalling pathways including increased cytosolic calcium levels. Here we show that transmembrane protein 33 (tmem33), which has no known function in multicellular organisms, is essential to mediate effects of VEGF in both zebrafish and human ECs. We find that tmem33 localises to the endoplasmic reticulum in zebrafish ECs and is required for cytosolic calcium oscillations in response to Vegfa. tmem33-mediated endothelial calcium oscillations are critical for formation of endothelial tip cell filopodia and EC migration. Global or endothelial-cell-specific knockdown of tmem33 impairs multiple downstream effects of VEGF including ERK phosphorylation, Notch signalling and embryonic vascular development. These studies reveal a hitherto unsuspected role for tmem33 and calcium oscillations in the regulation of vascular development.

The mechanosensitive Piezo1 channel: a three-bladed propeller-like structure and a lever-like mechanogating mechanism.

The evolutionarily conserved Piezo proteins, including Piezo1 and Piezo2, constitute a bona fide class of mechanosensitive (MS) cation channels, which play critical roles in various mammalian physiologies, including sensation of touch, proprioception and regulation of vascular development, and blood pressure. Furthermore, mutations in Piezos have been linked to various human genetic diseases, validating their potential as therapeutic targets. Thus, it is pivotal to understand how Piezo channels effectively convert mechanical force into selective cation permeation, and therefore precisely control the various mechanotransduction processes. On the basis of our recently determined cryoelectron microscopy structures of the full-length 2547-residue mouse Piezo1, structure-guided mutagenesis, and electrophysiological and pharmacological characterizations, here we focus on reviewing the key structural features and functional components that enable Piezo1 to employ a lever-like mechanogating mechanism to function as a sophisticated mechanotransduction channel.

Vascular pattern of the dentate gyrus is regulated by neural progenitors.

Neurogenesis is a vital process that begins during early embryonic development and continues until adulthood, though in the latter case, it is restricted to the subventricular zone and the subgranular zone of the dentate gyrus (DG). In particular, the DG's neurogenic properties are structurally and functionally unique, which may be related to its singular vascular pattern. Neurogenesis and angiogenesis share molecular signals and act synergistically, supporting the concept of a neurogenic niche as a functional unit between neural precursors cells and their environment, in which the blood vessels play an important role. Whereas it is well known that vascular development controls neural proliferation in the embryonary and in the adult brain, by releasing neurotrophic factors; the potential influence of neural cells on vascular components during angiogenesis is largely unknown. We have demonstrated that the reduction of neural progenitors leads to a significant impairment of vascular development. Since VEGF is a potential regulator in the neurogenesis-angiogenesis crosstalk, we were interested in assessing the possible role of this molecule in the hippocampal neurovascular development. Our results showed that VEGF is the molecule involved in the regulation of vascular development by neural progenitor cells in the DG.

Kidins220 and tumour development: Insights into a complexity of cross-talk among signalling pathways (Review).

The mechanistic complexes of kinase D-interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning (Kidins220/ARMS) bind and integrate a variety of cellular cues to mediate neuronal activities such as neuronal differentiation, survival, and cytoskeleton remodelling by interacting with a variety of binding partners. Accumulated evidence has also indicated its role in the regulation of vascular development. Mice with Kidins220 knockdown phenotypically present with cardiovascular abnormalities. Kidins220 also contributes to immunomodulation in combination with B cells and T cells. Moreover, emerging evidence has revealed that this protein regulates many crucial cellular processes and thus has been implicated in an increasing number of malignancies. Here, we review recent advances in our understanding of Kidins220 and its role in cancer development. Further investigation is warranted to shed light on the role played by Kidins220 in the dynamic arrangement of the cytoskeleton and epithelial–mesenchymal transition, and its implication in tumourigenesis and cancer progression.

Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.

Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.

Expression of vascular endothelial growth factor (VEGF) and factor VIII in the gilt placenta and its relation to fetal development

Vascular endothelial growth factor (VEGF) and von Willebrand factor (Factor VIII) are important components involved in the regulation of vascular development and identification of endothelial cells in many tissues. This study aimed to evaluate the presence of these substances in the placenta of pig fetuses located in different uterine regions and at different gestational ages and correlate them with fetal development. One hundred seventy-five pig fetuses from fifteen gilts slaughtered at 50, 80 and 106 days of pregnancy were used. Each uterine horn was divided into three segments, the apex, base and middle region, and also into left and right sides. The fetuses were sexed before determining their weight and anatomical measurements. The weights of the placentas were obtained for the calculation of placental efficiency, and VEGF and factor VIII were determined by immunohistochemistry. There was no significant interaction between gestational age, uterine segment or side and fetal sex in any of the variables studied. Higher VEGF and factor VIII concentrations were found at 80 and 105 days of pregnancy, and there was no significant difference between the right and left sides of the uterus, uterine segments or fetal sex. Positive correlations between VEGF and fetal weights were observed at 80 and 105 days of pregnancy, whereas factor VIII showed positive correlations with the weight and length of fetuses and placental weight and efficiency throughout pregnancy. It was concluded that VEGF and factor VIII are important growth factors associated with fetal development in pigs and are identified in all uterine segments. The concentration of these substances increases until the middle third of pregnancy which suggests that most of the uterine vascular development occurs before this stage.