Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling

Wilson, Christopher W.; Ye, Weilan

doi:10.4161/cam.28115

Cited by 38 publications

(32 citation statements)

References 77 publications

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“…A direct correlation of TGF-␤ effects on MMP9 as a potential cause of the blood-retinal barrier breakdown was already hypothesized (Behzadian et al, 2001). Small G-proteins (such as RAP1,which was identified in the transcriptomic differential analysis of BN-J rat) have also been reported to play a critical role in the stabilization of endothelial junctions (Wilson and Ye, 2014). Several studies have also established the role of growth factors (in particular VEGF) and inflammation in the pathophysiology of the MacTel 2 disease.…”

Section: Discussionmentioning

confidence: 96%

A New CRB1 Rat Mutation Links Müller Glial Cells to Retinal Telangiectasia

et al. 2015

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Section: Discussionmentioning

confidence: 96%

A New CRB1 Rat Mutation Links Müller Glial Cells to Retinal Telangiectasia

et al. 2015

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“…Activation of the EPAC-Rap1 pathway contributes to endothelium barrier properties through junction complex maintenance (41) and down-regulation of small G-protein RhoA, known to be involved in permeability (42). EPAC activation in HUVEC leads to the recruitment of VE-cadherin to the cell border and formation of long linear and continuous adherens junctions (24).…”

Section: Discussionmentioning

confidence: 99%

The EPAC–Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability

Ramos

Lin

Liu

et al. 2018

Journal of Biological Chemistry

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Increased retinal vascular permeability contributes to macular edema, a leading cause of vision loss in eye pathologies such as diabetic retinopathy, age-related macular degeneration, and central retinal vein occlusions. Pathological changes in vascular permeability are driven by growth factors such as VEGF and pro-inflammatory cytokines such as TNF-α. Identifying the pro-barrier mechanisms that block vascular permeability and restore the blood-retinal barrier (BRB) may lead to new therapies. The cAMP-dependent guanine nucleotide exchange factor (EPAC) exchange-protein directly activated by cAMP promotes exchange of GTP in the small GTPase Rap1. Rap1 enhances barrier properties in human umbilical endothelial cells by promoting adherens junction assembly. We hypothesized that the EPAC-Rap1 signaling pathway may regulate the tight junction complex of the BRB and may restore barrier properties after cytokine-induced permeability. Here, we show that stimulating EPAC or Rap1 activation can prevent or reverse VEGF- or TNF-α-induced permeability in cell culture and Moreover, EPAC activation inhibited VEGF receptor (VEGFR) signaling through the Ras/MEK/ERK pathway. We also found that Rap1B knockdown or an EPAC antagonist increases endothelial permeability and that VEGF has no additive effect, suggesting a common pathway. Furthermore, GTP-bound Rap1 promoted tight junction assembly, and loss of Rap1B led to loss of junctional border organization. Collectively, our results indicate that the EPAC-Rap1 pathway helps maintain basal barrier properties in the retinal vascular endothelium and activation of the EPAC-Rap1 pathway may therefore represent a potential therapeutic strategy to restore the BRB.

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“…This is described as angiogenesis, which is different from vasculogenesis. 27 Vasculogenesis is a process in which endothelial progenitor cells aggregate into cords, followed by lumen formation. This process requires at least 21 days to form a functional vessel.…”

Section: Discussionmentioning

confidence: 99%

Vasculature Characterization of a Multiterritory Perforator Flap: An Experimental Study

Wang

Zhou

Yang

et al. 2017

J reconstr Microsurg

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Tip necrosis in the perforator flap is a significant problem in clinical practice. This study aimed to characterize the vasculature of a multiterritory perforator flap using a rat model and to investigate the impact of the vasculature on flap survival. In total, 105 Sprague Dawley rats were divided into seven groups, including the control, 3 hours postoperative (PO), 12 hours PO, 1 day PO, 3 days PO, 5 days PO, and 7 days PO. A perforator flap with three territories based on the deep iliac circumflex artery was performed. Flaps with only skin incisions and vessel exposure were performed in the control group. The first choke zone (FCZ) was located between the anatomical and dynamic territories, and the second choke zone (SCZ) was located between the dynamic and potential territories. Sodium fluorescein and lead oxide-gelatin angiography and histological examination were performed in each group. Sodium fluorescein angiography revealed delayed staining in the perforator flap PO, particularly in the FCZ and SCZ. The delay phenomenon disappeared after 12 hours PO in the FCZ and after 1 day PO in the SCZ. Nonfluorescein-stained areas were found distal to the potential territory. In the FCZ PO, the choke vessels were dilated, while the number of microvessels was increased in the SCZ without choke vessel dilation. The remodeling of choke vessels and increase in microvessel number represent arteriogenesis and angiogenesis, respectively. This neovascularization was responsible for flap survival in the entire dynamic territory and part of the potential territory.

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Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling

Cited by 38 publications

References 77 publications

A New CRB1 Rat Mutation Links Müller Glial Cells to Retinal Telangiectasia

A New CRB1 Rat Mutation Links Müller Glial Cells to Retinal Telangiectasia

The EPAC–Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability

Vasculature Characterization of a Multiterritory Perforator Flap: An Experimental Study

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