Silencing of directional migration in roundabout4 knockdown endothelial cells

Kaur, Sukhbir; Samant, Ganesh V.; Pramanik, Kallal; Loscombe, Philip W; Pendrak, Michael L.; Roberts, D. A.; Ramchandran, Ramani

doi:10.1186/1471-2121-9-61

Cited by 46 publications

(62 citation statements)

References 36 publications

(75 reference statements)

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“…Though Slit2 was reported to inhibit angiogenesis (46,55), particularly in response to VEGF (34,35), the role of Slit signaling in angiogenesis remains controversial, as other studies reported that Slit proteins, including Slit2, can promote angiogenesis (37,38,63,69). Therefore, we tested the effect of Slit2 on vascular remodeling as a single agent, in the absence of VEGF.…”

Section: Slit2 Promotes Angiogenic Remodeling In Culture and In Vivomentioning

confidence: 99%

“…These interactions link Slit-Robo signaling to cytoskeletal remodeling, which promotes chemotaxis or chemorepulsion downstream of Robo signaling, depending upon the cell type and physiologic context (reviewed in references 28 and 43). Identified originally in Drosophila melanogaster (reviewed in reference 20) and later in vertebrates (12,47), the role of Slit proteins in regulation of angiogenesis is controversial, with reports of both proangiogenic (37,38,63,69,75) and antiangiogenic (26,34,35,46,55) activity. Relatively few studies have examined the role of Slit2 as a single agent in angiogenesis, though in the context of vascular endothelial growth factor (VEGF) (34,35,46,55), recent investigations have clearly demonstrated that Slit2 inhibits VEGF-induced vascular remodeling.…”

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confidence: 99%

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Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

Dunaway

Hwang

Lindsley

et al. 2011

Molecular and Cellular Biology

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Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro-and antiangiogenic activity. We report here that cooperation between Slit2 and ephrin-A1 regulates a balance between the pro-and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of ephrin-A1, providing a plausible mechanism for the pro-versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms. Angiogenesis, the process by which new blood vessels sprout from preexisting vessels, is critical for proper embryonic development and normal tissue homeostasis and contributes to the pathogenesis of many diseases, including cancer. Proper vessel morphogenesis requires a balance between angiogenic stimuli, which regulate endothelial cell invasion and migration, proliferation, and tubulogenesis, and angiostatic factors that terminate or inhibit these processes upon vessel maturation to promote vascular stability (reviewed in references 13, 14, 24, and 58). Members of the Slit/roundabout (Robo) gene family have recently emerged as key regulators of vascular remodeling and homeostasis, particularly with the discovery of an endothelial cell-specific Robo receptor, Robo4/Magic roundabout (reviewed in reference 43).The three Slit proteins (Slit1-3) identified in vertebrates interact with receptors of the Robo family (Robo1-4), Robo1 and Robo4 being most highly expressed in endothelial cells (76). While Robo receptors lack intrinsic kinase activity, the intracellular portions of the receptors contain several conserved CC motifs that can interact with intracellular kinases, such as Abelson kinase (Abl) and its substrate enabled (Ena), as well as GTPase activating proteins (GAPs) that modulate the activities of Rho family GTPases. These interactions link Slit-Robo signaling to cytoskeletal remodeling, which promotes chemotaxis or chemorepulsion downstream of Robo signaling, depending upon the cell type and physiologic context (reviewed in references 28 and 43). Identified originally in Drosophila melanogaster (reviewed in reference 20) and later in vertebrates (12, 47), the role of Slit proteins in regulation of angiogenesis is controversial, with reports of both proangiogenic (37, 38, 63, 69, 75) and antiangiogenic (26, 34, 35, 46, 55) activity....

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Section: Slit2 Promotes Angiogenic Remodeling In Culture and In Vivomentioning

confidence: 99%

mentioning

confidence: 99%

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

Dunaway

Hwang

Lindsley

et al. 2011

Molecular and Cellular Biology

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“…8 Robo4 is uniquely expressed in endothelial cells and its ligand is Slit2. 23,25 The Robo4/Slit2 signaling pathway has recently been identified as a regulator of microvascular maturation, endothelial permeability, and angiogenesis. [67][68][69] Our ongoing studies suggest that Robo4 protein is significantly decreased in the cerebral microvasculature of diabetic GK rats that develop erratic and dysfunctional angiogenesis (unpublished data).…”

Section: Diabetes and Neovascularizationmentioning

confidence: 99%

“…[23][24][25] Tip cells also inhibit stalk cells from becoming tip cells via the Notch-Delta like ligand (deltall) system and again this is dynamically regulated. These tube-like structures are stabilized and become capillaries by Ang-1-mediated recruitment of pericytes and basement membrane deposition.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

Ergul

Abdelsaid

Fouda

et al. 2014

J Cereb Blood Flow Metab

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Neovascularization is an innate physiologic response by which tissues respond to various stimuli through collateral remodeling (arteriogenesis) and new vessel formation from existing vessels (angiogenesis) or from endothelial progenitor cells (vasculogenesis). Diabetes has a major impact on the neovascularization process but the response varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. How diabetes influences cerebral neovascularization remained unresolved until recently. Diabetes is also a major risk factor for stroke and poor recovery after stroke. In this review, we discuss the impact of diabetes, stroke, and diabetic stroke on cerebral neovascularization, explore potential mechanisms involved in diabetes-mediated neovascularization as well as the effects of the diabetic milieu on poststroke neovascularization and recovery, and finally discuss the clinical implications of these effects.

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“…SLITs have been shown to both attract (2-6) and repel (7-9) endothelial cells. ROBO1, which binds directly to SLITs, has been shown to promote endothelial cell motility, either alone (2,6,10) or as a heterodimeric partner with ROBO4 (5,9). In contrast, ROBO4 binds SLITs at either very low affinity or not at all and likely requires a coreceptor, such as ROBO1 or a Syndecan, to signal (5,11,12).…”

mentioning

confidence: 99%

Vascular Robo4 restricts proangiogenic VEGF signaling in breast

Marlow

Binnewies

Sorensen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Formation of the vascular system within organs requires the balanced action of numerous positive and negative factors secreted by stromal and epithelial cells. Here, we used a genetic approach to determine the role of SLITs in regulating the growth and organization of blood vessels in the mammary gland. We demonstrate that vascularization of the gland is not affected by loss of Slit expression in the epithelial compartment. Instead, we identify a stromal source of SLIT, mural cells encircling blood vessels, and show that loss of Slit in the stroma leads to elevated blood vessel density and complexity. We examine candidate SLIT receptors, Robo1 and Robo4, and find that increased vessel angiogenesis is phenocopied by loss of endothelial-specific Robo4, as long as it is combined with the presence of an angiogenic stimulus such as preneoplasia or pregnancy. In contrast, loss of Robo1 does not affect blood vessel growth. The enhanced growth of blood vessels in Robo4 −/− endothelium is due to activation of vascular endothelial growth factor (VEGF)-R2 signaling through the Src and FAK kinases. Thus, our studies present a genetic dissection of SLIT/ROBO signaling during organ development. We identify a stromal, rather than epithelial, source of SLITs that inhibits blood vessel growth by signaling through endothelial ROBO4 to down-regulate VEGF/ VEGFR2 signaling.angiogenesis | ROBO | SLIT | mammary gland | organogenesis

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Silencing of directional migration in roundabout4 knockdown endothelial cells

Cited by 46 publications

References 36 publications

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

Vascular Robo4 restricts proangiogenic VEGF signaling in breast

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