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: 13.77). 05/2011; 121(5):1974-85. DOI: 10.1172/JCI44900
Source: PubMed

ABSTRACT 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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    • "Amongst the class 3 semaphorins, SEMA3E is the only family member known to directly bind and signal through a plexin, independently of neuropilins [61]. Thus, SEMA3E is expressed highly in mouse embryo somites and prevents hypersprouting of blood vessels and regulates vascular regrowth in retinopathy models by signalling to PLXND1 [49] [61] [64]. Together, these observations suggest that class 3 semaphorins are potential therapeutic targets in diseases driven by pathological vessel growth or vascular permeability. "
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    ABSTRACT: The neuropilins NRP1 and NRP2 are transmembrane proteins that regulate many different aspects of vascular and neural development. Even though they were originally identified as adhesion molecules, they are most commonly studied as co-receptors for secreted signalling molecules of the class 3 semaphorin (SEMA) and vascular endothelial growth factor (VEGF) families. During nervous system development, both classes of ligands control soma migration, axon patterning and synaptogenesis in the central nervous system, and they additionally help to guide the neural crest cell precursors of neurons and glia in the peripheral nervous system. Both classes of neuropilin ligands also control endothelial cell behaviour, with NRP1 acting as a VEGF-A isoform receptor in blood vascular endothelium and as a semaphorin receptor in lymphatic valve endothelium, and NRP2 promoting lymphatic vessel growth induced by VEGF-C. Here we provide an overview of neuropilin function in neurons and neural crest cells, discuss current knowledge of neuropilin signalling in the vasculature and conclude with a summary of neuropilin roles in cancer.
    Seminars in Cell and Developmental Biology 01/2013; 24(3). DOI:10.1016/j.semcdb.2013.01.001 · 5.97 Impact Factor
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    • "The tufts consist of activated endothelial cells and resemble pathological neovascularization observed in human proliferative retinopathies (Stahl et al. 2010). It has been shown that most endothelial cells from these tufts extend numerous filopodia (Budd et al. 2009; Fukushima et al. 2011; Hakansson et al. 2011; Zhang W et al. 2011). In contrast to tip cells in developmental angiogenesis , pathologically generated tip cells extend shorter filopodia, which grow in all directions (Fig. 2B). "
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    ABSTRACT: Endothelial tip cells are leading cells at the tips of vascular sprouts coordinating multiple processes during angiogenesis. In the developing retina, tip cells play a tightly controlled timely role in angiogenesis. In contrast, excessive numbers of tip cells are a characteristic of the chaotic pathological blood vessels in proliferative retinopathies. Tip cells control adjacent endothelial cells in a hierarchical manner to form the stalk of the sprouting vessel, using, amongst others, the VEGF-DLL-Notch signaling pathway, and recruit pericytes. Tip cells are guided towards avascular areas by signals from the local extracellular matrix, released by cells from the neuroretina such as astrocytes. Recently, tip cells were identified in endothelial cell cultures, enabling identification of novel molecular markers and mechanisms involved in tip cell biology. These mechanisms are relevant for understanding proliferative retinopathies. Agents which primarily target tip cells can block pathological angiogenesis in the retina efficiently and safely without adverse effects. A striking example is platelet-derived growth factor (PDGF), which was recently shown to be an efficacious additional target in the treatment of retinal neovascularization. Here we discuss these and other tip cell based strategies with respect to their potential to treat patients with ocular diseases dominated by neovascularization.
    Journal of Histochemistry and Cytochemistry 10/2012; 61. DOI:10.1369/0022155412467635 · 2.40 Impact Factor
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    • "We have recently shown that Sema3E- PlexinD1 signalling triggers two distinct pathways in cancer cells and in cells of the tumour microenvironment (Casazza et al, 2010). On one hand, endothelial cells and developing vessels are typically repelled by Sema3E, acting as an anti-angiogenic factor through PlexinD1 signalling (Casazza et al, 2010); this pathway seems to implicate an endothelial-specific regulation of the GTPases Arf6 (Sakurai et al, 2010) and RhoJ (Fukushima et al, 2011), affecting integrin-mediated adhesion and cytoskeletal remodelling. In cancer cells instead, Sema3E signalling promotes invasiveness and metastatic spreading in vivo, and this activity is mediated by the trans-activation of erythroblastic leukemia viral oncogene homolog 2 (ErbB2)-epidermal growth factor receptor (EGFR) oncogenic tyrosine kinase receptors (Casazza et al, 2010). "
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    ABSTRACT: Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.
    EMBO Molecular Medicine 03/2012; 4(3):234-50. DOI:10.1002/emmm.201100205 · 8.25 Impact Factor
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