Investigation of the Regulation of Roundabout4 by Hypoxia-Inducible Factor-1α in Microvascular Endothelial Cells

Tian, Rui; Liu, Zaoxia; Zhang, Hui; Fang, Xuexun; Wang, Chenguang; Qi, Shounan; Cheng, Yan; Su, Guanfang

doi:10.1167/iovs.14-14409

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…The formation of fibrovascular membranes (FVMs) is the hallmark of PDR, which causes serious vision loss in patients. Robo4 colocalized with HIF-1α and VEGF in the vessels of FVMs and its expression increased in FVMs [117,118], indicating that it might play a role in the formation of FVMs. Under hypoxic conditions, HIF-1α positively regulated the transcription of Robo4 to promote the invasion and proliferation of HRECs [117].…”

Section: Robo4 and Ocular Neovascularizationmentioning

confidence: 94%

“…Robo4 colocalized with HIF-1α and VEGF in the vessels of FVMs and its expression increased in FVMs [117,118], indicating that it might play a role in the formation of FVMs. Under hypoxic conditions, HIF-1α positively regulated the transcription of Robo4 to promote the invasion and proliferation of HRECs [117]. Under hyperglycemic conditions, increased transcription of SP1 up-regulated the levels of Robo4 to increase the migration, permeability and angiogenesis of HRECs [59].…”

Section: Robo4 and Ocular Neovascularizationmentioning

confidence: 94%

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Regulatory mechanisms of Robo4 and their effects on angiogenesis

et al. 2019

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Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Roundabout (Robo) family of axon guidance molecules. Robo4 is an endothelial-specific receptor that participates in endothelial cell migration, proliferation, and angiogenesis and the maintenance of vasculature homeostasis. The purpose of this review is to summarize and analyze three main mechanisms related to the expression and function of Robo4 during developmental and pathological angiogenesis. In this review, static shear stress and the binding of transcription factors such as E26 transformation-specific variant 2 (ETV2) and Slit3 induce Robo4 expression and activate Robo4 during tissue and organ development. Robo4 interacts with Slit2 or UNC5B to maintain vascular integrity, while a disturbed flow and the expression of transcription factors in inflammatory or neoplastic environments alter Robo4 expression levels, although these changes have uncertain functions. Based on the mechanisms described above, we discuss the aberrant expression of Robo4 in angiogenesis-related diseases and propose antiangiogenic therapies targeting the Robo4 signaling pathway for the treatment of ocular neovascularization lesions and tumors. Finally, although many problems related to Robo4 signaling pathways remain to be resolved, Robo4 is a promising and potentially valuable therapeutic target for treating pathological angiogenesis and developmental defects in angiogenesis.

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Section: Robo4 and Ocular Neovascularizationmentioning

confidence: 94%

Section: Robo4 and Ocular Neovascularizationmentioning

confidence: 94%

Regulatory mechanisms of Robo4 and their effects on angiogenesis

et al. 2019

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“…However, in pathogenic angiogenesis, Robo4 has been found to accelerate the progression of angiogenesis [18]. In our previous study, Robo4 was found upregulated in human retinal endothelial cells under hypoxia and overexpressed in the FVMs from proliferative diabetic retinopathy (PDR) patients [19]. Recently, studies have been carried out on the interdependent roles of VEGF and Robo4 during angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Upregulated VEGF and Robo4 correlate with the reduction of miR-15a in the development of diabetic retinopathy

Gong

Xie

et al. 2019

Endocrine

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Purpose Vascular endothelial growth factor (VEGF) plays implicated roles in diabetic retinopathy (DR). The role of roundabout 4 (Robo 4) in angiogenesis and vasculogenesis is controversial; however, the interdependent relationship between these two factors has not been studied in DR. This study determined the colocalization of VEGF and Robo4 in fibrovascular membranes (FVM) from patients with proliferative diabetic retinopathy (PDR). MicroRNA (miRNA)-mediated modulation of VEGF and Robo4 was explored in diabetic rats and ARPE-19 tissue culture cells under hyperglycemia. Methods VEGF and Robo4 co-expression in the FVM was analyzed using immunofluorescence. VEGF and Robo4 levels were determined in diabetic retinas and ARPE-19 tissue culture cells under high glucose using western blotting and RT-qPCR. MicroRNA agomir was intraocularly injected to increase miR-15a expression and downregulate VEGF and Robo4 levels in diabetic retinas. Results VEGF and Robo4 colocalization in FVM vessels was observed. Increased VEGF levels were consistent in diabetic retinas and ARPE-19 tissue culture cells cultured under hyperglycemia. Robo4 decreased in ARPE-19 tissue culture cells exposed to hyperglycemia for 72 h, whereas it increased in diabetic rat retinas. Several miRNAs were differentially expressed during DR progression. Furthermore, miR-15a agomir injection inhibited high levels of VEGF and Robo4 in diabetic retinas. Conclusions VEGF and Robo4 were co-expressed in FVMs from PDR patients. In the early stages of DR, VEGF was upregulated and contributed to DR development, whereas, in the late stage of DR, VEGF and Robo4 worked together to aggravate DR progression. However, miR-15a could downregulate VEGF and Robo4 to ameliorate DR development.

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“…If the retinal blood vessels in Phase I formed normally, the malignant proliferation of blood vessels caused by peripheral retinal ischemia in phase II can be avoided [3], thus ROP children could obtain better visual function. Studies have shown that human retinal angiogenesis is related to the proliferation, migration and angiogenesis of microvascular endothelial cells [2,22], the HMEC-1 is a recognized model of vascular endothelial cells [11,23]. Therefore, we established a model of HMEC-1 induced by 40% hyperoxia in vitro to simulate the relatively hyperoxia environment of phase I ROP, and found that the biological behaviors of HMEC-1 such as cell proliferation, migration and angiogenesis were inhibited in 40% hyperoxia environment.…”

Section: Discussionmentioning

confidence: 98%

Heme relieves the inhibition of proliferation, migration and angiogenesis of HMEC-1 under hyperoxia by inhibiting BACH1

Jian¹,

Mei²,

Yuan³

2020

Preprint

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Background The relatively hyperoxia inhibited vascular endothelial growth factor (VEGF) in retina is the main cause of angiogenesis retardation in phase I retinopathy of prematurity (ROP). Human retinal angiogenesis is related to the proliferation, migration and angiogenesis of microvascular endothelial cells. Previous studies have confirmed that BTB and CNC homology l (BACH1) can inhibit VEGF and angiogenesis, while heme can specifically degrade BACH1. However, the effect of heme on endothelial cells and ROP remains unknown. Methods In this report, we established a model of human microvascular endothelial cells (HMEC-1) induced by 40% hyperoxia to simulate the relatively hyperoxia of phase I ROP. Meanwhile, heme was added to investigate the effects on the growth and viability of HMEC-1. Cell counting kit 8 (CCK8) and 5-ethynyl-2′-deox-yuridine (EDU) methods were used to detect the proliferation ability. Cell scratch test and matrigel matrix glue were used to detect the migration or angiogenesis ability. Western blot and immunofluorescence methods were used to detect the relative protein expression of BACH1 and VEGF. Results The proliferation, migration and angiogenesis of HMEC-1 were inhibited under hyperoxia. Moderate heme can promote endothelial cell proliferation, while excessive can inhibit, 20 µM heme could inhibit the expression of BACH1, promote the expression of VEGF, and relieve the inhibition of proliferation, migration and angiogenesis induced by hyperoxia in HMEC-1. Conclusions 20 µM heme can relieve the inhibitory effects induced by hyperoxia, via the mechanism of promoting VEGF by inhibiting BACH1 in HMEC-1, and maybe a potential medicine for retinal angiogenesis retardation induced by relatively hyperoxia in phase I ROP.

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Investigation of the Regulation of Roundabout4 by Hypoxia-Inducible Factor-1α in Microvascular Endothelial Cells

Cited by 17 publications

References 30 publications

Regulatory mechanisms of Robo4 and their effects on angiogenesis

Regulatory mechanisms of Robo4 and their effects on angiogenesis

Upregulated VEGF and Robo4 correlate with the reduction of miR-15a in the development of diabetic retinopathy

Heme relieves the inhibition of proliferation, migration and angiogenesis of HMEC-1 under hyperoxia by inhibiting BACH1

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