Mammalian Target of Rapamycin (mTOR) is Activated in Cutaneous Vascular Malformations <i>in Vivo</i>

Shirazi, Farheen; Cohen, Cynthia; Fried, Levi; Arbiser, Jack L.

doi:10.1089/lrb.2007.1012

Cited by 56 publications

(37 citation statements)

References 22 publications

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“…Indeed, VEGF-B targeting by genetic deletion, neutralizing antibody or shRNA inhibited both choroidal and retinal neovascularization. VEGF-B therefore may be an important target in antiangiogenic therapy and VEGF-B blockade may have clinical implications in treating different types of vascular malformations, such as hemangioma (28,29).…”

Section: Discussionmentioning

confidence: 99%

VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis

Zhang

Tang

et al. 2009

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

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VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a ''survival,'' rather than an ''angiogenic'' factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases.apoptosis ͉ vascular survival ͉ ocular neovascularization

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Section: Discussionmentioning

confidence: 99%

VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis

Zhang

Tang

et al. 2009

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

255

200

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“…Embryonic vasculogenesis is important both in its own right and for its potential relevance for adult processes such as malformations. [42][43][44] It will be of considerable interest to relate ecscr to the hierarchy of known signals responsible for the generation of the initial vasculature in fish and mammals.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell–specific chemotaxis receptor (ecscr) promotes angioblast migration during vasculogenesis and enhances VEGF receptor sensitivity

Verma

Bhattacharya

Remadevi

et al. 2010

Blood

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Endothelial cell-specific chemotaxis receptor (ECSCR) is a cell surface protein expressed by blood endothelial cells with roles in endothelial cell migration and signal transduction. We investigated the function of ecscr in the development of the zebrafish vasculature. Zebrafish ecscr is expressed in angioblasts and in axial vessels during angioblast migration and vasculogenesis. Morpholino-directed ecscr knockdown resulted in defective angioblast migration in the posterior lateral plate mesoderm, a process known to depend on vascular endothelial-derived growth factor (VEGF). In cultured cells, transfected ECSCR localized to actin-rich membrane protrusions, colocalizing with kinase insert domain protein receptor (KDR)/VEGF receptor 2 in these regions. ECSCR-silenced cells show reduced VEGF-induced phosphorylation of KDR but not of FMS-like tyrosine kinase 1 (FLT1)/VEGF receptor 1. Finally, chemical inhibition of VEGF receptor activity in zebrafish resulted in angioblast deficiencies that partially overlap with those seen in ecscr morphants. We propose that ecscr promotes migration of zebrafish angioblasts by enhancing endothelial kdr sensitivity to VEGF.

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“…Recently, we demonstrated that overexpression of Akt in endothelial cells could reproduce the large vessel phenotype. Interestingly, while there is evidence that hemangiomas also have high levels of Akt, they also express reactive oxygen markers such as ICAM-1 and Wilms tumor 1 (WT-1), while hemangiomas do not (70)(71)(72). Thus, large vessel vascular malformations use Akt, while hemangiomas use both Akt and reactive oxygen.…”

Section: Angiogenesis and Vascular Lesionsmentioning

confidence: 99%

Application of Angiogenesis to Clinical Dermatology

Fried

Arbiser

2008

Advances in Dermatology

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Mammalian Target of Rapamycin (mTOR) is Activated in Cutaneous Vascular Malformations in Vivo

Abstract: Endothelial expression of Akt is responsible for tumor responsiveness to rapamycin. We demonstrate that expression of phosphorylated S6 is elevated in specimens. Our findings provide a rationale for clinical trials of rapamycin on Sturge-Weber or Klippel-Trenaunay-Weber patients.

Cited by 56 publications

References 22 publications

VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis

VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis

Endothelial cell–specific chemotaxis receptor (ecscr) promotes angioblast migration during vasculogenesis and enhances VEGF receptor sensitivity

Application of Angiogenesis to Clinical Dermatology

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