Abstract
ObjectivesTo testify that endothelial cells (ECs) induce astrocyte maturation by leukaemia inhibitory factor (LIF) secretion.Materials and MethodsIn vivo experiments, mice bearing floxed alleles of YAP were crossed with mice expressing a Cre recombinase driven by the endothelial Tek promoter (Tek‐Cre) to finally obtain the following three genotypes: YAP f/f, Tek‐Cre; YAP f/w, Tek‐Cre; and YAP f/f. Retinal vascularization and astrocyte network were evaluated by whole‐mount fluorescence and Western blotting. In vitro, experiments were performed in an astrocyte and human microvascular endothelial cell (HMEC‐1) coculture model to analyse the mechanisms underlying the effect of endothelial YAP on astrocytes.ResultsIn vivo, YAPf/f;Tek‐Cre mice showed delayed angiogenesis, sparse vessels and decreased glial fibrillary acidic protein (GFAP)+ astrocytes but aberrant growth of endothelial networks and immature astrocytes (platelet‐derived growth factor A, PDGFRA+ astrocytes) overgrowth. In vitro, Yap deletion attenuated the LIF release that delayed the maturation of retinal astrocyte which was consistent with the results of HMEC‐1—astrocyte coculture. The effect of YAP overexpression on LIF‐LIFR axis in HMEC‐1 interferes the GFAP expression of astrocyte. In contrast, LIF protein rescues the astrocytic GFAP expression when EC YAP was inhibited by siRNAs.ConclusionsWe show that EC yes‐associated protein (YAP) is not only a critical coactivator of Hippo signalling in retinal vessel development but also plays an essential role in retinal astrocyte maturation by regulating LIF production.
Highlights
The dynamic interactions between astrogliogenesis and blood vessel growth in physiological and pathological conditions have long been of interest
Our study found that the expression of immature retinal astrocytes gradually decreased from embryonic day 16 (E16) to postnatal day 21 (P21) which was consistent with the expression pattern of yes-associated protein (YAP) in retinal development (Figure 3A)
Since astrocytes form a reticular network that appears to provide a substrate for endothelial cells (ECs) migration, they have long been proposed to guide angiogenesis.[27]
Summary
The dynamic interactions between astrogliogenesis and blood vessel growth in physiological and pathological conditions have long been of interest. The physiological and pathological conditions of vessels contribute to astrocyte differentiation, which is critically important in glial-neurovascular unit development and pathology.[8] Delayed vascularization leads to abnormal astrocyte behaviour and endothelial cell (EC) networks in the mouse retina.[8,9] Recent studies have demonstrated that the transcriptional coactivator yes-associated protein (YAP) affects EC development and angiogenesis. In this study, using Tek-Cre; YAPf/f mice, we showed that retinal vascularization and astrocyte maturation were retarded depending on endothelial LIF-astrocytic LIFR behaviour These mechanisms of the interactions between retinal vessels and astrocytes provide potential therapeutic targets for retinal neovascularization
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