Eph-B4 prevents venous adaptive remodeling in the adult arterial environment

Muto, Akihito; Yi, Tai; Harrison, Kathryn; Dávalos, Alberto; Fancher, Tiffany T.; Ziegler, Kenneth R.; Feigel, Amanda; Kondo, Yuka; Nishibe, Toshiya; Sessa, William C.; Dardik, Alan

doi:10.1084/jem.20101854

Cited by 55 publications

(96 citation statements)

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“…24 Downstream regulators of Eph-B4 signaling in the endothelial cell include Akt, ERK1/2 25,26 and caveolin-1. 8 Our finding that eNOS is phosphorylated with stimulation of Eph-B4 in adult venous endothelial cells is consistent with previous reports that have shown that activation of Eph-B4 enhances NO production in endothelial cells in vitro. 8,25 We previously showed that reduced endothelial Eph-B4 signaling in endothelial cells derived from heterozygous Eph-B4 mice 27 was associated with diminished basal levels of eNOS protein expression and NO production but increased tube formation, 15 consistent with our data in vitro (Figure 3), but emphasizing the differences between endothelial cell function in vitro and in 3-dimensions, especially during vein graft adaptation in vivo.…”

Section: Discussionsupporting

confidence: 93%

“…[19][20][21][22] We have previously shown that Eph-B4 expression is diminished during vein graft adaptation in adults, suggesting that successful vein graft adaptation, characterized by increased venous wall thickness and adaptive outward remodeling, is associated with loss of venous identity. 7,8 Our data also suggests that Eph-B4 is a negative regulator of eNOS during vein graft adaptation in vivo, with reduced Eph-B4 expression during vein graft adaptation associated with enhanced eNOS phosphorylation after 3 weeks (Figure 4), although not at 1 week postoperatively, 15 consistent with successful vein graft adaptation at 3 weeks in this model. Improving vein graft adaptation with increased NO production has led to the use of eNOS as a potential therapeutic agent.…”

Section: Discussionsupporting

confidence: 67%

“…11,23 Interestingly, the vein graft vasa vasorum may be a source of eNOS promoting vein graft adaptation. 42 We reported that Eph-B4 regulates vein graft adaptation via caveolin-1, 8 and our data suggests that Eph-B4-caveolin-1 signaling may regulate downstream eNOS, a potential target for therapeutic modulation.…”

Section: Discussionmentioning

confidence: 73%

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Eph-B4 Mediates Vein Graft Adaptation By Regulation of eNOS

Wang

Collins

Bai

et al. 2015

Journal of Vascular Surgery

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Objectives-Vein graft adaptation is characterized by loss of expression of the tyrosine kinase receptor Eph-B4, the embryonic determinant of venous identity, without increased expression of its ligand Ephrin-B2, the embryonic determinant of arterial identity. eNOS is an important mediator of vessel remodeling. We hypothesized that the mechanism of action of Eph-B4 during vein graft adaptation might be via regulation of downstream eNOS activity. Methods-Mouse lung endothelial cells (MLEC)were stimulated with Ephrin-B2/Fc, without and with preclustering, without and with the eNOS inhibitor L-NAME or the Eph-B4 inhibitor NVP-BHG712, and assessed by Western blot and immunofluorescence for eNOS and Eph-B4 phosphorylation. Nitric oxide (NO) production was assessed using a NO-specific chemiluminescence analyzer. Cell migration was assessed using a transwell assay. Human and mouse vein graft specimens were examined for eNOS activity by Western blot, and vessel remodeling was assessed in vein grafts in wild-type (WT) or eNOS-knockout (KO) mice.Results-Ephrin-B2/Fc stimulated both Eph-B4 and eNOS phosphorylation in a bimodal temporal distribution (n=4; p<.05), with preclustered Ephrin-B2/Fc causing prolonged peak Eph-B4 and eNOS phosphorylation as well as altered subcellular localization (n=4; p<.05). Ephrin-B2/Fc increased NO release (n=3; p<.01) as well as increased endothelial cell migration (n=6; p<. 05) in an eNOS-dependent fashion. Both human and mouse vein grafts showed increased eNOS phosphorylation compared with normal veins (n=3; p<.05). Vein grafts from eNOS-KO mice showed less dilation and less wall thickening compared with WT vein grafts (n=7; p<.05).

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 67%

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Eph-B4 Mediates Vein Graft Adaptation By Regulation of eNOS

Wang

Collins

Bai

et al. 2015

Journal of Vascular Surgery

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“…17 EphB4 heterozygous-knockout (EphB4+/−) EC were similarly isolated from EphB4+/− mice (The Jackson Laboratory). 5 Primary EC were immortalized by infection with retrovirus encoding the middle T antigen, and propagated in EBM2/EGM-2 MV SingleQuot Kit Supplement & Growth Factors (Lonza) supplemented with 15% fetal bovine serum (Hyclone), Penicillin-streptomycin, and L-glutamine in 5% CO 2 at 37°C. Culture media was changed every 2 days.…”

Section: Methodsmentioning

confidence: 99%

“…diminished EphB4 expression without induction of EphrinB2 expression. 4–5 EphB4, a member of the trans-membrane receptor tyrosine kinase family is a determinant of venous fate during embryonic development, whereas its ligand EphrinB2 is a determinant of arterial fate; interestingly, both EphB4 and EphrinB2 persist on adult veins and arteries, respectively. 6–7 Although the functions of EphB4 and EphrinB2 in adult cells are unknown, we have previously shown that EphB4 inhibits neointimal thickening of vein grafts, suggesting an active role for EphB4 in the limitation of venous wall thickness in adult veins.…”

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confidence: 99%

Vascular endothelial growth factor-A inhibits EphB4 and stimulates delta-like ligand 4 expression in adult endothelial cells

Yang

Guo

Jadlowiec

et al. 2013

Journal of Surgical Research

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Background During vein graft adaptation to the arterial circulation, vascular endothelial growth factor (VEGF)-A expression transiently increases before becoming down-regulated; however the role of VEGF-A in venous remodeling is not clear. In addition, although VEGF-A stimulates angiogenesis and determines arterial identity in nascent arterial endothelial cells (EC), the role of VEGF-A in regulating identity in adult venous EC is also not clear. Materials and Methods EC, wild type (EphB4+/+) or heterozygous knockout (EphB4+/−), were stimulated with VEGF-A (0–100ng/ml) and examined with qPCR and Western blotting. Results VEGF-A (100ng/ml) inhibited expression of EphB4 and stimulated expression of dll4 but did not stimulate either notch or EphrinB2 expression in adult venous EC. Pretreatment with VEGFR2 neutralizing antibody abolished VEGF-stimulated down-regulation of EphB4 but not the up-regulation of Dll4. Pretreatment with PD98059 or wortmannin showed that VEGF-A down-regulation of EphB4 and up-regulation of dll4 are MEK-ERK-dependent but PI3k-Akt-independent. Compared to VEGF-induced EphB4 down-regulation and Dll4 up-regulation in control EC, reduced EphB4 signaling in EphB4+/− EC showed even further down-regulation of EphB4 and up-regulation of dll4. Conclusions Despite the genetic programming of arterial and venous EC fate, VEGF-A can repress venous identity in adult venous EC without induction of arterial identity. These changes in adult EC in vitro recapitulate the changes in identity described during vein graft adaptation to the arterial environment in vivo.

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Membrane‐mediated regulation of vascular identity

Hashimoto

Foster

Santana

et al. 2016

Birth Defects Research Pt C

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Vascular diseases span diverse pathology, but frequently arise from aberrant signaling attributed to specific membrane-associated molecules, particularly the Eph-ephrin family. Originally recognized as markers of embryonic vessel identity, Eph receptors and their membrane-associated ligands, ephrins, are now known to have a range of vital functions in vascular physiology. Interactions of Ephs with ephrins at cell-to-cell interfaces promote a variety of cellular responses such as repulsion, adhesion, attraction, and migration, and frequently occur during organ development, including vessel formation. Elaborate coordination of Eph-and ephrin-related signaling among different cell populations is required for proper formation of the embryonic vessel network. There is growing evidence supporting the idea that Eph and ephrin proteins also have postnatal interactions with a number of other membraneassociated signal transduction pathways, coordinating translation of environmental signals into cells. This article provides an overview of membrane-bound signaling mechanisms that define vascular identity in both the embryo and the adult, focusing on Eph-and ephrin-related signaling. We also discuss the role and clinical significance of this signaling system in normal organ development, neoplasms, and vascular pathologies.

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Eph-B4 prevents venous adaptive remodeling in the adult arterial environment

Abstract: Stimulation of Eph-B4 prevents adaptive remodeling and preserves venous identity when veins are surgically placed into an arterial environment.

Cited by 55 publications

References 50 publications

Eph-B4 Mediates Vein Graft Adaptation By Regulation of eNOS

Eph-B4 Mediates Vein Graft Adaptation By Regulation of eNOS

Vascular endothelial growth factor-A inhibits EphB4 and stimulates delta-like ligand 4 expression in adult endothelial cells

Membrane‐mediated regulation of vascular identity

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