RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice.
In adults, angiogenic abnormalities are involved in not only tumor growth but several human inherited diseases as well. It is unclear, however, concerning how the normal vascular structure is maintained and how angiogenesis is initiated in normal adults. Using the Cre-LoxP-mediated conditional gene deletion, we show in the present study that in adult mice disruption of the transcription factor recombination signal-binding protein Jkappa (RBP-J) in endothelial cells strikingly induced spontaneous angiogenesis in multiple tissues, including retina and cornea, as well as in internal organs, such as liver and lung. In a choroidal neovascularization model, which mimics the angiogenic process in tumor growth and age-related macular degeneration, RBP-J deficiency induced a more intensive angiogenic response to injury. This could be transmitted by bone marrow, indicating that RBP-J could modulate bone marrow-derived endothelial progenitor cells in adult angiogenesis. In addition, in the absence of RBP-J, proliferation of endothelial cells increased significantly, leading to accumulative vessel outgrowth. These findings suggest that in adults RBP-J-mediated Notch signaling may play an essential role in the maintenance of vascular homeostasis by repressing endothelial cell proliferation.
Dou
Guo-Rui
GR
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Xi'an 710032, China.
Wang
Yao-Chun
YC
Hu
Xing-Bin
XB
Hou
Li-Hong
LH
Wang
Chun-Mei
CM
Xu
Jian-Feng
JF
Wang
Yu-Sheng
YS
Liang
Ying-Min
YM
Yao
Li-Bo
LB
Yang
An-Gang
AG
Han
Hua
H
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D049109:Cell Proliferation; D002829:Choroid / Q000098:blood supply; D006706:Homeostasis / Q000187:drug effects; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008648:Mesoderm / Q000098:blood supply; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497762:Notch1 protein, mouse; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D040301:Vascular Endothelial Growth Factor Receptor-2