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A glycan-based approach to therapeutic angiogenesis.

ABSTRACT: Angiogenesis, the sprouting of new blood vessels from existing vasculature, involves multiple complex biological processes, and it is an essential step for hemostasis, tissue healing and regeneration. Angiogenesis stimulants can ameliorate human disease conditions including limb ischemia, chronic wounds, heart disease, and stroke. The current strategies to improve the bioavailability of pro-angiogenic growth factors, including VEGF and FGF2, have remained largely unsuccessful. This study demonstrates that small molecules, termed click-xylosides, can promote angiogenesis in the in vitro matrigel tube formation assay and the ex ovo chick chorioallantoic membrane assay, depending on their aglycone moieties. Xyloside treatment enhances network connectivity and cell survivability, thereby, maintaining the network structures on matrigel culture for an extended period of time. These effects were achieved via the secreted xyloside-primed glycosaminoglycans (GAG) chains that in part, act through an ERK1/2 mediated signaling pathway. Through the remodeling of GAGs in the extracellular matrix of endothelial cells, the glycan approach, involving xylosides, offers great potential to effectively promote therapeutic angiogenesis.

SUBMITTER: Chua JS

PROVIDER: S-EPMC5538652 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A glycan-based approach to therapeutic angiogenesis.

Chua Jie Shi JS Tran Vy M VM Kalita Mausam M Quintero Maritza V MV Antelope Orlando O Muruganandam Geethu G Saijoh Yukio Y Kuberan Balagurunathan B

PloS one 20170801 8

Angiogenesis, the sprouting of new blood vessels from existing vasculature, involves multiple complex biological processes, and it is an essential step for hemostasis, tissue healing and regeneration. Angiogenesis stimulants can ameliorate human disease conditions including limb ischemia, chronic wounds, heart disease, and stroke. The current strategies to improve the bioavailability of pro-angiogenic growth factors, including VEGF and FGF2, have remained largely unsuccessful. This study demonst ...[more]

PMID: 28763512

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Project description:PurposeNeovascular eye diseases, such as proliferative diabetic retinopathy (PDR), wet age-related macular degeneration (wAMD) and retinopathy of prematurity (ROP), are major causes of vision loss and blindness worldwide. Our transcription factor motif enrichment analysis highlighted RUNX1 as a key regulator in the hypoxic response. The purpose of this study was to characterize how loss of Runx1 affects physiological and pathological retinal vasculature formation.MethodsRNA-seq analysis and Transcription factor motif enrichment analysis were conducted in hypoxic and normoxic HUVECs. Conditional deletion of Runx1 in endothelial cells In mice was achieved using recombinase driver Cdh5-CreERT2. Vascular coverage, density, vessel progression, branchpoints, and sprout numbers was measured in retina of Runx1iECKO mice. The expression patterns, functions, and potential therapeutic value of RUNX1 were further explored with clinical samples, as well as in vivo and in vitro experiments. Bioinformatics and high-throughput sequencing were performed to identify potential target genes of Runx1. RT-qPCR and Western blot analyses were carried out to detect the changes of PI3-kinase/AKT/mTOR pathway.ResultsLoss of Runx1 in mice resulted in a reduction of the vascular coverage, density, vessel progression, branchpoints, and sprouts numbers of the retinal vascular network during its development. Notably, mature blood vessels remained unaffected by Runx1 inhibition. Upregulation of RUNX1 was observed in patients with PDR and ROP. RUNX1 Inhibition reduced endothelial cell proliferation, migration and tubule formation, leading to decreased pathological neovascularization, which is shown in oxygen-induced retinopathy. Mechanistically, in vitro experiments demonstrated that RUNX1 regulates EC angiogenesis through the PI3K/AKT/mTOR signaling pathway.ConclusionsRunx1 is essential for physiological retinal vascularization. RUNX1 Inhibition may effectively decrease pathological neovascularization. Our findings suggest that targeting RUNX1 could be a promising therapeutic strategy for retinal neovascular disorders, preserving the integrity of mature blood vessels while selectively inhibiting neovascularization.

Project description:Glycan permethylation was introduced as a tool to facilitate the study of glycans in 1903. Since that time, permethylation procedures have been continually modified to improve permethylation efficiency and qualitative applicability. Typically, however, either laborious preparation steps or cumbersome and uneconomical spin columns have been needed to obtain decent permethylation yields on small glycan samples. Here we describe a spin column-free (SCF) glycan permethylation procedure that is applicable to both O- and N-linked glycans and can be employed upstream to intact glycan analysis by MALDI-MS, ESI-MS, or glycan linkage analysis by GC-MS. The SCF procedure involves neutralization of NaOH beads by acidified phosphate buffer, which eliminates the risk of glycan oxidative degradation and avoids the use of spin columns. Optimization of the new permethylation procedure provided high permethylation efficiency for both hexose (>98%) and HexNAc (>99%) residues-yields which were comparable to (or better than) those of some widely-used spin column-based procedures. A light vs. heavy labelling approach was employed to compare intact glycan yields from a popular spin-column based approach to the SCF approach. Recovery of intact N-glycans was significantly better with the SCF procedure (p < 0.05), but overall yield of O-glycans was similar or slightly diminished (p < 0.05 for tetrasaccharides or smaller). When the SCF procedure was employed upstream to hydrolysis, reduction and acetylation for glycan linkage analysis of pooled glycans from unfractionated blood plasma, analytical reproducibility was on par with that from previous spin column-based "glycan node" analysis results. When applied to blood plasma samples from stage III-IV breast cancer patients (n = 20) and age-matched controls (n = 20), the SCF procedure facilitated identification of three glycan nodes with significantly different distributions between the cases and controls (ROC c-statistics > 0.75; p < 0.01). In summary, the SCF permethylation procedure expedites and economizes both intact glycan analysis and linkage analysis of glycans from whole biospecimens.

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A glycan-based approach to therapeutic angiogenesis.

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A glycan-based approach to therapeutic angiogenesis.

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