Apelin Is a Crucial Factor for Hypoxia-Induced Retinal Angiogenesis

Abstract

Objective-To investigate the role of endogenous apelin in pathological retinal angiogenesis. Methods and Results-The progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, mainly induced by vascular endothelial growth factor (VEGF) and erythropoietin. Although antiangiogenic therapies using anti-VEGF drugs are effective in treating retinal neovascularization, they show a transient efficacy and cause general adverse effects. New therapeutic target molecules are needed to resolve these issues. It was recently demonstrated that the apelin/APJ system, a newly deorphanized G protein-coupled receptor system, is involved in physiological retinal vascularization. Retinal angiography and mRNA expression were examined during hypoxia-induced retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Compared with age-matched control mice, retinal apelin expression was dramatically increased during the hypoxic phase in oxygen-induced retinopathy model mice. APJ was colocalized in proliferative cells, which were probably endothelial cells of the ectopic vessels in the vitreous body. Apelin deficiency hardly induced hypoxia-induced retinal angiogenesis despite the upregulation of VEGF and erythropoietin mRNA in oxygen-induced retinopathy model mice. Apelin small and interfering RNA suppressed the proliferation of endothelial cells independent of the VEGF/VEGF receptor 2 signaling pathway. Conclusion-These results suggest that apelin is a prerequisite factor for hypoxia-induced retinal angiogenesis. Key Words: angiogenesis Ⅲ VEGF Ⅲ apelin Ⅲ retinopathy T he progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, which is mainly induced by vascular endothelial growth factor (VEGF) 1 and erythropoietin (Epo). 2 Antiangiogenic therapies targeting these factors are effective in treating proliferative diabetic retinopathy. 3,4 However, these therapies show a transient efficacy and cause the general adverse effects. 5 Furthermore, elevated VEGF levels do not necessarily correlate with pathological retinal angiogenesis in patients with diabetic maculopathy. 6 This suggests that the entire process of pathological retinal angiogenesis includes more than just upregulation of VEGF expression. Therefore, finding other factors involved in pathological retinal angiogenesis is important.The apelin/apelin receptor (APJ) system is a newly deorphanized G protein-coupled receptor system. 7 Recently, much attention has been focused on the possible roles of the apelin/APJ system in vascular pathophysiology. 8,9 APJ is expressed in endothelial cells at the leading edge of vessels during early embryogenesis; and apelin, in combination with VEGF, induces the proliferation and assembly of endothelial cells. 10 Moreover, we demonstrated a retardation of physiological retinal vascular development during the early postnatal period and a reduced angiogenic response to VEGF in apelin-knockout...

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…Significantly, apelin is required for the normal development of frog heart (Cox et al 2006, Inui et al 2006 and formation of murine blood vessels (Kidoya & Takakura 2012). Additionally, the development of the retinal vasculature is stunted in apelin KO mice (Kasai et al 2008), and apelin is necessary for hypoxia-induced retinal angiogenesis (Kasai et al 2010), and is also involved in non-neovascular remodelling of the retina (McKenzie et al 2012). The apelinergic system has been implicated in tumour neoangiogenesis.…”

Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K/Akt and MEK/Erk pathways

“…During recent years, apelin has gained increasing attention in the function of angiogenesis, especially in retinal neovascularization. Kasai and others' studies [4,5] found that apelin is a crucial factor for retinal angiogenesis in prematurity of retinopathy (ROP) mice and apelin-deficiency can retard the retinal vascular development. In in vivo study, the sizes of the laser induced CNV lesions in apelin-KO or APJ-KO mice decreased significantly compared with those in the WT mice [6].…”

Effect of apelin on mitosis, apoptosis and DNA repair enzyme OGG 1/2 expression in intestinal cell lines IEC-6 and Caco-2

“…Furthermore, it was reported [14] that treatment of human umbilical vein endothelial cells with apelin increased endothelial cell migration and proliferation in a dose-dependent manner. Apelin suppressed the proliferation of endothelial cells independently of the vascular endothelial growth factor VEGF/VEGF receptor and appeared to be a prerequisite factor for hypoxia-induced retinal angiogenesis [21]. Based on these results, it seems that apelin can affect the cell cycle interacting with phosphatidylinositol 3 kinase (PI3-K) pathway activity, but more detailed data are needed to determine the signalling pathway involved in apelin action in IEC-6 and Caco-2 cell lines used in our study.…”

“…The apelin was found to stimulate [12][13][14][15] or inhibit [21] cell proliferation, depending on a cell line. Wang and co-workers [9] showed that apelin stimulated cell proliferation in human gastric epithelial cell line SIIA, while Han et al, [22] reported that acute exposure of rat pups to hypoxia decreased gastric and colonic epithelial cell proliferation, while hypoxia in combination with apelin administration resulted in increased proliferation of epithelial cells and improved cell survival [22].…”