Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice

Timothy R. Carlson, Yibing Yan, Xiaoqing Wu, Michael T. Lam, Gale L. Tang, Levi J. Beverly, Louis M. Messina, Anthony J Capobianco, Zena Werb, Rong Wang

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Direct communication between arteries and veins without intervening capillary beds is the primary pathology of arteriovenous malformations (AVMs). Although Notch signaling is implicated in embryonic arteriovenous (AV) differentiation, its function in the adult mammalian vasculature has not been established due to the embryonic lethality that often occurs in both gain- and loss-of-function mutants. We expressed a constitutively active Notch4, int3, in the adult mouse endothelium by using the tetracycline-repressible system to suppress int3 during embryogenesis. int3 caused profound blood vessel enlargement and AV shunting, which are hallmarks of AVM, and led to lethality within weeks of its expression. Vessel enlargement, a manifestation of AVM, occurred in an apparently tissue-specific fashion; the liver, uterus, and skin were affected. int3-mediated vascular defects were accompanied by arterialization, including ectopic venous expression of ephrinB2, increased smooth muscle cells, and up-regulation of endogenous Notch signaling. Remarkably, the defective vessels and illness were reversed upon repression of int3 expression. Finally, endothelial expression of a constitutively active Notch1 induced similar hepatic vascular lesions. Our results provide gain-of-function evidence that Notch signaling in the adult endothelium is sufficient to render arterial characteristics and lead to AVMs.

Original languageEnglish
Pages (from-to)9884-9889
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number28
DOIs
StatePublished - Jul 12 2005
Externally publishedYes

Fingerprint

Arteriovenous Malformations
Blood Vessels
Endothelium
Liver
Tetracycline
Uterus
Smooth Muscle Myocytes
Embryonic Development
Veins
Up-Regulation
Arteries
Communication
Pathology
Skin

Keywords

  • Angiogenesis
  • Arterialization
  • Notch
  • Signaling
  • Vascular remodeling

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. / Carlson, Timothy R.; Yan, Yibing; Wu, Xiaoqing; Lam, Michael T.; Tang, Gale L.; Beverly, Levi J.; Messina, Louis M.; Capobianco, Anthony J; Werb, Zena; Wang, Rong.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 28, 12.07.2005, p. 9884-9889.

Research output: Contribution to journalArticle

Carlson, Timothy R. ; Yan, Yibing ; Wu, Xiaoqing ; Lam, Michael T. ; Tang, Gale L. ; Beverly, Levi J. ; Messina, Louis M. ; Capobianco, Anthony J ; Werb, Zena ; Wang, Rong. / Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 28. pp. 9884-9889.
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