Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
The Journal of clinical investigation (Impact Factor: 13.22). 05/2011; 121(5):1974-85. DOI: 10.1172/JCI44900
Source: PubMed


During development, the retinal vasculature grows toward hypoxic areas in an organized fashion. By contrast, in ischemic retinopathies, new blood vessels grow out of the retinal surfaces without ameliorating retinal hypoxia. Restoration of proper angiogenic directionality would be of great benefit to reoxygenize the ischemic retina and resolve disease pathogenesis. Here, we show that binding of the semaphorin 3E (Sema3E) ligand to the transmembrane PlexinD1 receptor initiates a signaling pathway that normalizes angiogenic directionality in both developing retinas and ischemic retinopathy. In developing mouse retinas, inhibition of VEGF signaling resulted in downregulation of endothelial PlexinD1 expression, suggesting that astrocyte-derived VEGF normally promotes PlexinD1 expression in growing blood vessels. Neuron-derived Sema3E signaled to PlexinD1 and activated the small GTPase RhoJ in ECs, thereby counteracting VEGF-induced filopodia projections and defining the retinal vascular pathfinding. In a mouse model of ischemic retinopathy, enhanced expression of PlexinD1 and RhoJ in extraretinal vessels prevented VEGF-induced disoriented projections of the endothelial filopodia. Remarkably, intravitreal administration of Sema3E protein selectively suppressed extraretinal vascular outgrowth without affecting the desired regeneration of the retinal vasculature. Our study suggests a new paradigm for vascular regeneration therapy that guides angiogenesis precisely toward the ischemic retina.

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    • "It was first identified in 2000 (Vignal et al., 2000) and early studies suggested roles for RhoJ in modulating the actin cytoskeleton, early endocytosis and adipocyte differentiation (Abe et al., 2003; Aspenström et al., 2004; de Toledo et al., 2003; Nishizuka et al., 2003; Vignal et al., 2000). Subsequently it was found to be expressed in endothelial cells (Fukushima et al., 2011; Kaur et al., 2011; Takase et al., 2012; Yuan et al., 2011) and induced by the transcription factor Erg (Yuan et al., 2011). Functionally, RhoJ has been shown to regulate endothelial motility, tubulogenesis and lumen formation in vitro (Kaur et al., 2011; Yuan et al., 2011) and vascularisation in vivo (Kim et al., 2014; Takase et al., 2012; Yuan et al., 2011). "
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    ABSTRACT: RhoJ is a RhoGTPase expressed in endothelial cells and tumour cells which regulates cell motility, invasion, endothelial tube formation and focal adhesion numbers. This study aimed to further delineate the molecular function of RhoJ. Using timelapse microscopy RhoJ was found to regulate focal adhesion disassembly; siRNA-mediated knockdown of RhoJ increased focal adhesion disassembly time, while expression of an active mutant (daRhoJ) decreased it. Further, daRhoJ co-precipitated with the GIT-PIX complex, a regulator of focal adhesion disassembly. An interaction between daRhoJ and GIT1 was confirmed using yeast-2-hybrid, which depended on the Spa homology domain of GIT1. GIT1, GIT2, β-PIX and RhoJ all co-localised in focal adhesions and depended on each other for their recruitment to focal adhesions. Functionally, the GIT-PIX complex regulated endothelial tube formation, with knockdown of GIT1/2 or β-PIX phenocopying RhoJ knockdown. RhoJ knockout mice showed reduced tumour growth and diminished tumour vessel density, identifying a role for RhoJ in mediating tumour angiogenesis. These studies give novel insight into the molecular function of RhoJ in regulating cell motility and tumour vessel formation.
    Journal of Cell Science 06/2014; 127(14). DOI:10.1242/jcs.140434 · 5.43 Impact Factor
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    • "In an oxygen-induced retinopathy (OIR) model that represents neoangiogenesis in ischemic retinas [50], intraocular anti-VEGF drugs suppress not only the extraretinal neoangiogenesis but also the desirable regeneration of intraretinal vessels, resulting in the deterioration of retinal ischemia [40]. These experimental results raise caution for the clinical use of anti-VEGF drugs in the treatment of proliferative DR. "
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    ABSTRACT: Vision loss in diabetic retinopathy (DR) is attributable to retinal vascular disorders that result in macular edema and neoangiogenesis. In addition to laser photocoagulation therapy, intraocular injections of antivascular endothelial growth factor drugs have contributed to the treatment of these disease conditions. Nonetheless, the clinical feasibility of intraocular drug administration has raised an increasing demand to develop alternative drugs that can fundamentally ameliorate the retinal vascular dysfunctions in DR. For this purpose, experimental animal models that reproduce human DR would be of clinical benefit. Despite the unavailability of DR models in rats or mice, pharmacological and genetic manipulations without hyperglycemia have successfully recapitulated retinal edema and neoangiogenesis in postnatal mouse retinas, thereby enabling the understanding of the pathophysiology underlying DR. This article highlights the utility of experimental mouse models of retinal vascular abnormalities and discusses cellular and molecular mechanisms responsible for the onset and progression of DR. These approaches will lead to the identification of novel drug targets for the restoration of vascular integrity and regeneration of functional capillaries in DR.
    Diabetes & metabolism journal 08/2013; 37(4):217-24. DOI:10.4093/dmj.2013.37.4.217
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    • "Whether similar mechanisms operate in endothelial cells to modulate SEMA3E signaling is not known. Remarkably, SEMA3E normalizes VEGF-A-induced pathological vessel growth in a mouse model of oxygen-induced retinopathy, in which retinal vessels grow abnormally into the vitreous [84]. Thus, the intravitreal administration of SEMA3E protein prevented this abnormal vessel growth and instead normalized vessel growth within the retina. "
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    ABSTRACT: The developing central nervous system (CNS) is vascularized via ingression of blood vessels from the outside as the neural tissue expands. This angiogenic process occurs without perturbing CNS architecture due to exquisite cross-talk between the neural compartment and invading blood vessels. Subsequently, this intimate relationship also promotes the formation of the neurovascular unit that underlies the blood-brain barrier and regulates blood flow to match brain activity. This review provides a historical perspective on research into CNS blood vessel growth and patterning, discusses current models used to study CNS angiogenesis, and provides an overview of the cellular and molecular mechanisms that promote blood vessel growth and maturation. Finally, we highlight the significance of these mechanisms for two different types of neurovascular CNS disease.
    Cellular and Molecular Life Sciences CMLS 03/2013; 70(10). DOI:10.1007/s00018-013-1277-5 · 5.81 Impact Factor
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