Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7.
Epidermal growth factor-like domain 7 (Egfl7) is important for regulating tubulogenesis in zebrafish, but its role in mammals remains unresolved. We show here that endothelial overexpression of Egfl7 in transgenic mice leads to partial lethality, hemorrhaging, and altered cardiac morphogenesis. These defects are accompanied by abnormal vascular patterning and remodeling in both the embryonic and postnatal vasculature. Egfl7 overexpression in the neonatal retina results in a hyperangiogenic response, and EGFL7 knockdown in human primary endothelial cells suppresses endothelial cell proliferation, sprouting, and migration. These phenotypes are reminiscent of Notch inhibition. In addition, our results show that EGFL7 and endothelial-specific NOTCH physically interact in vivo and strongly suggest that Egfl7 antagonizes Notch in both the postnatal retina and in primary endothelial cells. Specifically, Egfl7 inhibits Notch reporter activity and down-regulates the level of Notch target genes when overexpressed. In conclusion, we have uncovered a critical role for Egfl7 in vascular development and have shown that some of these functions are mediated through modulation of Notch signaling.
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Donna
D
Nichol
Carrie
C
Shawber
Michael J
MJ
Fitch
Kathryn
K
Bambino
Anshula
A
Sharma
Jan
J
Kitajewski
Heidi
H
Stuhlmann
D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D066255:EGF Family of Proteins; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006321:Heart / Q000196:embryology; D006470:Hemorrhage / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D011506:Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C479627:Egfl7 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D008156:Luciferases