Inhibition of Semaphorin As a Novel Strategy for Therapeutic Angiogenesis

Moriya, Junji; Minamino, Tohru; Tateno, Kaoru; Okada, Sho; Uemura, Akiyoshi; Shimizu, Ippei; Yokoyama, Masataka; Nojima, Aika; Okada, Mitsuhiro; Koga, Hisashi; Komuro, Issei

doi:10.1161/circresaha.109.210815

Cited by 67 publications

(64 citation statements)

References 31 publications

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“…These data indicate that the inhibitory function of Sema3E in endothelial cells is dependent on the R-Ras GAP activity of Plexin D1 and on their prominent expression of Rnd2. Altogether, these data are consistent with the reported restrictive role of Sema3E in developmental and postischemic angiogenesis (20,22) and with our in vivo data indicating inhibition of tumor vasculature.…”

Section: Sema3e-dependent Endothelial Cell Repulsion Relies On Rnd2-esupporting

confidence: 92%

“…Genetic evidence showed that Sema3E-Plexin D1 signaling is required in developmental angiogenesis (20,21). Moreover, recent evidence indicates that Sema3E is implicated in regulating postischemic angiogenesis (22). Intriguingly, while Plexin D1 expression is generally low in normal adult tissues, it is elevated in endothelial cells of tumor vessels and in cancer cells (23,24).…”

Section: Introductionmentioning

confidence: 99%

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Sema3E–Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

Casazza¹,

Finisguerra²,

Capparuccia³

et al. 2010

J. Clin. Invest.

168

159

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Semaphorin 3E (Sema3E) is a secreted molecule implicated in axonal path finding and inhibition of developmental and postischemic angiogenesis. Sema3E is also highly expressed in metastatic cancer cells, but its mechanistic role in tumor progression was not understood. Here we show that expression of Sema3E and its receptor Plexin D1 correlates with the metastatic progression of human tumors. Consistent with the clinical data, knocking down endogenous expression of either Sema3E or Plexin D1 in human metastatic carcinoma cells hampered their metastatic potential when injected into mice, while tumor growth was not markedly affected. Conversely, overexpression of exogenous Sema3E in cancer cells increased their invasiveness, transendothelial migration, and metastatic spreading, although it inhibited tumor vessel formation, resulting in reduced tumor growth in mice. The proinvasive and metastatic activity of Sema3E in tumor cells was dependent on transactivation of the Plexin D1-associated ErbB2/Neu oncogenic kinase. In sum, Sema3E-Plexin D1 signaling in cancer cells is crucially implicated in their metastatic behavior and may therefore be a promising target for strategies aimed at blocking tumor metastasis.

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Section: Sema3e-dependent Endothelial Cell Repulsion Relies On Rnd2-esupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Sema3E–Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

Casazza¹,

Finisguerra²,

Capparuccia³

et al. 2010

J. Clin. Invest.

168

159

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“…In this scenario, the ability PIP5K1␤ to act downstream from Plexin-D1 and both upstream and downstream of GEP100-Arf6 may help explain the rapid and potent activation of Arf6 by Plexin-D1 and its dramatic impact on FA disassembly, integrin internalization, and cellular collapse caused by Sema3E on endothelial cells (10). Although the existence of this proposed positive feedback loop may warrant further investigation, given the remarkable antiangiogenic activity of Sema3E (10,30,45), we can also speculate that the activation of PIP5K1␤-GEP100-Arf6 signaling circuitry may ultimately provide new biochemical targets for pharmacological intervention in many disease conditions characterized by aberrant angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein

Sakurai

Jian

Lee

et al. 2011

Journal of Biological Chemistry

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The semaphorins are a family of secreted or membranebound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells. Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADPribosylation factor 6), which regulates intracellular trafficking of ␤1 integrin. However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells. We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrinmediated focal adhesions and endothelial cell collapse. Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration.Angiogenesis, the formation of new blood capillaries from pre-existing ones, is an essential process during embryonic development. In adults, angiogenesis is required for tissue repair during physiological wound healing, whereas dysregulated angiogenesis contributes to a variety of pathological conditions, such as diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and cancer (1). Hence, the identification of molecular mechanisms controlling normal and aberrant angiogenesis may afford new therapeutic opportunities for multiple human diseases (2). In this regard, recent studies revealed that axon guidance molecules, including netrin, slit, eph, and semaphorins, play a key role in developmental and postnatal angiogenesis (3). Among them, multiple secreted class III semaphorins (Sema3s) 4 are reported to control endothelial cell migration in vitro and in vivo (4 -7). Sema3s signal through A-type and D-type Plexin family proteins (Plexin-A1, -A2, and -A3 and Plexin-D1) and utilize their coreceptor neuropilins (Nrp1 and Nrp2) to tightly control proand antiangiogenic responses (8). However, the downstream signaling pathways initiated by these semaphorin receptors are complex and not fully understood,...

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“…PlexinD1-Fc protein was purified using a HiTrap Protein G column (GE Healthcare) from serum-free culture supernatants of FreeStyle 293F cells (Invitrogen) transfected with a plasmid vector expressing the extracellular domain of mouse PlexinD1 (Met1-Gly1266) fused to the Fc fragment of human IgG under control of the CAG promoter (20). Recombinant PlexinD1-Fc, mouse VEGFR1-human Fc (R&D Systems), human Fc (Jackson ImmunoResearch Laboratories Inc.), and human Sema3E (R&D Systems) proteins in sterile buffer were injected into the vitreous humor using glass capillary pipettes with a micromanipulator (Drummond Scientific Co.).…”

Section: Methodsmentioning

confidence: 99%

“…To determine the role of PlexinD1 signaling in retinal vascular development, we pharmacologically neutralized its endogenous ligands by intravitreal injection of its soluble protein, PlexinD1-Fc (20). Five hours after PlexinD1-Fc injection at P5, we observed an increase in the length and number of endothelial filopodia, both at the tips and in the stalks of the sprouting vessels ( Figure 2, A and B).…”

Section: Ecs Express Plexind1 In Response To Vegf Signaling In the Dementioning

confidence: 99%

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

Fukushima¹,

Okada²,

Kataoka³

et al. 2011

J. Clin. Invest.

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191

272

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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. Neuronderived 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 VEGFinduced 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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Inhibition of Semaphorin As a Novel Strategy for Therapeutic Angiogenesis

Cited by 67 publications

References 31 publications

Sema3E–Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

Sema3E–Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein

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

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