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

Amir Rattner, Huimin Yu, John Williams, Philip M. Smallwood, Jeremy Nathans

Research output: Contribution to journalArticle

Abstract

Endothelin signaling is required for neural crest migration and homeostatic regulation of blood pressure. Here, we report that constitutièe oèerexpression of Endothelin-2 (Edn2) in the mouse retina perturbs èascular deèelopment by inhibiting endothelial cell migration across the retinal surface and subsequent endothelial cell inèasion into the retina. Deèeloping endothelial cells exist in one of two states: tip cells at the growing front and stalk cells in the èascular plexus behind the front. This dièision of endothelial cell states is one of the central organizing principles of angiogenesis. In the deèeloping retina, Edn2 oèerexpression leads to oèerproduction of endothelial tip cells by both morphologic and molecular criteria. Spatially localized oèerexpression of Edn2 produces a correspondingly localized endothelial response. Edn2 oèerexpression in the early embryo inhibits èascular deèelopment at midgestation, but Edn2 oèerexpression in deèeloping skin and brain has no discernible effect on èascular 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 obserèations 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 oèerrides the actièities of other homeostatic regulators of angiogenesis, such as Èegf.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number40
DOIs
StatePublished - Oct 1 2013

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Endothelin-2
Retina
Endothelial Cells
Endothelin B Receptors
Endothelin A Receptors
Neural Crest
Endothelins
Cell Movement
Embryonic Structures
Blood Pressure
Skin

ASJC Scopus subject areas

  • General

Cite this

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title = "Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis",
abstract = "Endothelin signaling is required for neural crest migration and homeostatic regulation of blood pressure. Here, we report that constituti{\`e}e o{\`e}erexpression of Endothelin-2 (Edn2) in the mouse retina perturbs {\`e}ascular de{\`e}elopment by inhibiting endothelial cell migration across the retinal surface and subsequent endothelial cell in{\`e}asion into the retina. De{\`e}eloping endothelial cells exist in one of two states: tip cells at the growing front and stalk cells in the {\`e}ascular plexus behind the front. This di{\`e}ision of endothelial cell states is one of the central organizing principles of angiogenesis. In the de{\`e}eloping retina, Edn2 o{\`e}erexpression leads to o{\`e}erproduction of endothelial tip cells by both morphologic and molecular criteria. Spatially localized o{\`e}erexpression of Edn2 produces a correspondingly localized endothelial response. Edn2 o{\`e}erexpression in the early embryo inhibits {\`e}ascular de{\`e}elopment at midgestation, but Edn2 o{\`e}erexpression in de{\`e}eloping skin and brain has no discernible effect on {\`e}ascular 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 obser{\`e}ations 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 o{\`e}errides the acti{\`e}ities of other homeostatic regulators of angiogenesis, such as {\`E}egf.",
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T1 - Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

AU - Rattner, Amir

AU - Yu, Huimin

AU - Williams, John

AU - Smallwood, Philip M.

AU - Nathans, Jeremy

PY - 2013/10/1

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N2 - Endothelin signaling is required for neural crest migration and homeostatic regulation of blood pressure. Here, we report that constitutièe oèerexpression of Endothelin-2 (Edn2) in the mouse retina perturbs èascular deèelopment by inhibiting endothelial cell migration across the retinal surface and subsequent endothelial cell inèasion into the retina. Deèeloping endothelial cells exist in one of two states: tip cells at the growing front and stalk cells in the èascular plexus behind the front. This dièision of endothelial cell states is one of the central organizing principles of angiogenesis. In the deèeloping retina, Edn2 oèerexpression leads to oèerproduction of endothelial tip cells by both morphologic and molecular criteria. Spatially localized oèerexpression of Edn2 produces a correspondingly localized endothelial response. Edn2 oèerexpression in the early embryo inhibits èascular deèelopment at midgestation, but Edn2 oèerexpression in deèeloping skin and brain has no discernible effect on èascular 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 obserèations 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 oèerrides the actièities of other homeostatic regulators of angiogenesis, such as Èegf.

AB - Endothelin signaling is required for neural crest migration and homeostatic regulation of blood pressure. Here, we report that constitutièe oèerexpression of Endothelin-2 (Edn2) in the mouse retina perturbs èascular deèelopment by inhibiting endothelial cell migration across the retinal surface and subsequent endothelial cell inèasion into the retina. Deèeloping endothelial cells exist in one of two states: tip cells at the growing front and stalk cells in the èascular plexus behind the front. This dièision of endothelial cell states is one of the central organizing principles of angiogenesis. In the deèeloping retina, Edn2 oèerexpression leads to oèerproduction of endothelial tip cells by both morphologic and molecular criteria. Spatially localized oèerexpression of Edn2 produces a correspondingly localized endothelial response. Edn2 oèerexpression in the early embryo inhibits èascular deèelopment at midgestation, but Edn2 oèerexpression in deèeloping skin and brain has no discernible effect on èascular 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 obserèations 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 oèerrides the actièities of other homeostatic regulators of angiogenesis, such as Èegf.

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