Dataset Information

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae.

ABSTRACT:

Background

Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We hypothesize that EphrinB2 signaling is active during AVF maturation and may be a mechanism of venous remodeling.

Methods

Aortocaval fistulae were created or sham laparotomy was performed in C57Bl/6 mice, and specimens were examined on Days 7 or 21. EphrinB2 reverse signaling was activated with EphB4-Fc applied periadventitially in vivo and in endothelial cell culture medium in vitro. Downstream signaling was assessed using immunoblotting and immunofluorescence.

Results

Venous remodeling during AVF maturation was characterized by increased expression of EphrinB2 as well as Akt1, extracellular signal-regulated kinases 1/2 (ERK1/2), and p38. Activation of EphrinB2 with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and was associated with increased diameter and wall thickness in the AVF. Both mouse and human endothelial cells treated with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and increased endothelial cell tube formation and migration.

Conclusions

Activation of EphrinB2 signaling by EphB4-Fc was associated with adaptive venous remodeling in vivo while activating endothelial cell function in vitro. Regulation of EphrinB2 signaling may be a new strategy to improve AVF maturation and patency.

SUBMITTER: Wang T

PROVIDER: S-EPMC8024410 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae.

Wang Tun T Liu Jia J Liu Haiyang H Lee Shin-Rong SR Gonzalez Luis L Gorecka Jolanta J Shu Chang C Dardik Alan A

The Journal of surgical research 20201007

<h4>Background</h4>Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We ...[more]

PMID: 33039109

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Project description:Background: Although clinical outcome of arteriovenous fistula (AVF) as a preferred vascular access for hemodialysis has been inadequate, biological mechanisms of AVF maturation and failure is still poorly understood. Since our mouse AVF model recapitulates human AVF maturation and partial failure, we hypothesized that high throughput RNA sequencing (RNA-seq) analysis would identify early changes in gene expression that might predict AVF maturation and failure. Method: Aortocaval fistula creation (AVF group) or sham operation (sham group) was performed with C57BL/6 mice (10 wk). Ultrasound was performed to confirm the AVF patency and to measure hemodynamics. Venous limbs were collected on postoperative day 7 and total RNA was extracted. After Poly-A mRNA libraries were constructed, RNA-seq was performed. Differentially expressed genes (DEG) were identified, and subsequent enrichment analyses of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed with bioinformatics techniques. Results: 1057 DEG were identified between the AVF and sham groups. Genes in metabolic pathways were significantly downregulated in the AVF. Since gene expression patterns among the AVF group were significantly heterogenous, the AVF group was divided into 2 groups (‘normal’ AVF group; nAVF and ‘outliers’ group; OUT), and subgroup analyses were performed. Although physiological data of body weight change and hemodynamics were not different between the nAVF and OUT groups, 413 DEG were identified between them. Enrichment analyses showed significant overrepresentation of metabolism, immunity, and coagulation in the OUT group. Comparing the nAVF group with the sham group, 403 DEG were identified. Enrichment analyses showed increase of gene expression related to cell cycle, extracellular matrix, and immunity. Comparing these results with previously published data, the gene expression patterns of the nAVF group was consistent with AVF maturation and adaptive remodeling, whereas the OUT group showed attenuated difference, suggesting the heterogeneity of the AVF group reflects early gene expression changes in the process of AVF maturation and failure. Significant sex differences were not observed in the AVF group. Conclusions: A small subset of AVF undergoes aberrant biological processes in the early phase including diminished ECM remodeling, activated coagulation and upregulated metabolism, that could lead to fistula failure. Detection of these processes might be a viable translational strategy to predict fistula failure and reduce patient morbidity.

Dataset Information

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae.

Background

Methods

Results

Conclusions

Publications

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae.

Similar Datasets

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