Identification and functional analysis of endothelial tip cell–enriched genes

Toro, R.; Prahst, Claudia; Mathivet, Thomas; Siegfried, Géraldine; Kaminker, Joshua S.; Larrivée, Bruno; Bréant, Christiane; Duarte, António; Takakura, Nobuyuki; Fukamizu, Akiyoshi; Penninger, Josef; Eichmann, Anne

doi:10.1182/blood-2010-02-270819

Cited by 405 publications

(437 citation statements)

References 50 publications

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“…More interestingly, the stalk cell markers Tie2 and Apj (the G protein-coupled receptor for Apln) were underrepresented in the Z/Edn2;Six3-Cre retina transcriptome as were the transporters Slco1c1 and Slc38a5 (mediators of thyroid hormone and neutral amino acid uptake, respectively) and transcription factor Sox17, which was suggested by earlier work to be a regulator of retinal vascular development in response to Norrin/Fz4 signaling (24). The tip cell markers Apln and Esm1 (21,25) were overrepresented in the Z/Edn2;Six3-Cre retina transcriptome along with Vegfa, which was expected for an hypoxic retina (Fig. 4 B and C).…”

Section: Resultsmentioning

confidence: 95%

“…4 D and L). In cross-sections of the midcentral retina, Dll4 and Ang2 transcripts, both of which are normally enriched in tip cells (21), are present at the vitreal face of Z/Edn2;Six3-Cre but undetectable in the corresponding region of control retinas (Fig. 4 E and F).…”

Section: Resultsmentioning

confidence: 99%

“…As noted in the Introduction, in the radially expanding early postnatal retinal vasculature, there are two morphologically and molecularly distinct classes of endothelial cells (5,21). Tip cells are located at the growing front, produce numerous filopodia, and lack a lumen.…”

Section: Resultsmentioning

confidence: 99%

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Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

Rattner

Williams

et al. 2013

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

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Endothelin signaling is required for neural crest migration and homeostatic regulation of blood pressure. Here, we report that constitutive overexpression of Endothelin-2 (Edn2) in the mouse retina perturbs vascular development by inhibiting endothelial cell migration across the retinal surface and subsequent endothelial cell invasion into the retina. Developing endothelial cells exist in one of two states: tip cells at the growing front and stalk cells in the vascular plexus behind the front. This division of endothelial cell states is one of the central organizing principles of angiogenesis. In the developing retina, Edn2 overexpression leads to overproduction of endothelial tip cells by both morphologic and molecular criteria. Spatially localized overexpression of Edn2 produces a correspondingly localized endothelial response. Edn2 overexpression in the early embryo inhibits vascular development at midgestation, but Edn2 overexpression in developing skin and brain has no discernible effect on vascular structure. Inhibition of retinal angiogenesis by Edn2 requires expression of Endothelin receptor A but not Endothelin receptor B in the neural retina. Taken together, these observations imply that the neural retina responds to Edn2 by synthesizing one or more factors that promote the endothelial tip cell state and inhibit angiogenesis. The response to Edn2 is sufficiently potent that it overrides the activities of other homeostatic regulators of angiogenesis, such as Vegf.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

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Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

Rattner

Williams

et al. 2013

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

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“…4a,b). Despite the strongly compromised sprouting and radial outgrowth, expression of Esm1, a tip cell marker that is induced by VEGF-A 21,22 , was maintained in a fraction of EC at the angiogenic growth front ( Supplementary Fig. 4c).…”

Section: Inducible Inactivation Of Itgb1 In the Postnatal Endotheliummentioning

confidence: 99%

Integrin β1 controls VE-cadherin localization and blood vessel stability

et al. 2015

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Angiogenic blood vessel growth requires several distinct but integrated cellular activities. Endothelial cell sprouting and proliferation lead to the expansion of the vasculature and give rise to a highly branched, immature plexus, which is subsequently reorganized into a mature and stable network. Although it is known that integrin-mediated cell-matrix interactions are indispensable for embryonic angiogenesis, little is known about the function of integrins in different steps of vascular morphogenesis. Here, by investigating the integrin b1-subunit with inducible and endothelial-specific gene targeting in the postnatal mouse retina, we show that b1 integrin promotes endothelial sprouting but is a negative regulator of proliferation. In maturing vessels, integrin b1 is indispensable for proper localization of VE-cadherin and thereby cell-cell junction integrity. The sum of our findings establishes that integrin b1 has critical functions in the growing and maturing vasculature, and is required for the formation of stable, non-leaky blood vessels.

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“…VEGF produced by hypoxic retinal astrocytes leads to tip cell migration via VEGFR2 . Tip cells show characteristic gene expression profiles (Del Toro et al 2010;Strasser et al 2010) and produce high levels of the Notch ligand Dll4, which signals to adjacent cells expressing Notch receptors to suppress tip cell formation, such that they become follower "stalk" cells, proliferating ECs that form the capillary lumen and allow blood transport and tissue oxygenation. Stalk cells down-regulate expression of VEGFR2 and VEGFR3 and increase levels of the decoy receptor VEGFR1, altogether becoming less sensitive to VEGF (Hellstrom et al 2007;Suchting et al 2007;Tammela et al 2008).…”

Section: Development and Maturation Of Cns Vesselsmentioning

confidence: 99%

Molecular Parallels between Neural and Vascular Development

Eichmann

Thomas

2012

Cold Spring Harbor Perspectives in Medicine

114

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The human central nervous system (CNS) features a network of 400 miles of blood vessels that receives .20% of the body's cardiac output and uses most of its blood glucose. Many human diseases, including stroke, retinopathy, and cancer, are associated with the biology of CNS blood vessels. These vessels originate from extrinsic cell populations, including endothelial cells and pericytes that colonize the CNS and interact with glia and neurons to establish the blood -brain barrier and control cerebrovascular exchanges. Neurovascular interactions also play important roles in adult neurogenic niches, which harbor a unique population of neural stem cells that are intimately associated with blood vessels. We here review the cellular and molecular mechanisms required to establish the CNS vascular network, with a special focus on neurovascular interactions and the functions of vascular endothelial growth factors.

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Identification and functional analysis of endothelial tip cell–enriched genes

Abstract: Sprouting of developing blood vessels is

Cited by 405 publications

References 50 publications

Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

Integrin β1 controls VE-cadherin localization and blood vessel stability

Molecular Parallels between Neural and Vascular Development

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