Myc regulates embryonic vascular permeability and remodeling.
Previous work has shown that c-Myc is required for adequate vasculogenesis and angiogenesis. To further investigate the contribution of Myc to these processes, we conditionally expressed c-Myc in embryonic endothelial cells using a tetracycline-regulated system. Endothelial Myc overexpression resulted in severe defects in the embryonic vascular system. Myc-expressing embryos undergo widespread edema formation and multiple hemorrhagic lesions. They die between embryonic days 14.5 and 17.5. The changes in vascular permeability are not caused by deficiencies in vascular basement membrane composition or pericyte coverage. However, the overall turnover of endothelial cells is elevated as is revealed by increased levels of both proliferation and apoptosis. Whole-mount immunohistochemical analysis revealed alterations in the architecture of capillary networks. The dermal vasculature of Myc-expressing embryos is characterized by a reduction in vessel branching, which occurs despite upregulation of the proangiogenic factors vascular endothelial growth factor-A and angiopoietin-2. Thus, the net outcome of an excess of vascular endothelial growth factor-A and angiopoietin-2 in the face of an elevated cellular turnover appears to be a defect in vascular integrity.
Kokai
Enikö
E
Institute of Physiological Chemistry, Ulm University, Ulm, Germany.
Voss
Florian
F
Fleischer
Frank
F
Kempe
Sybille
S
Marinkovic
Dragan
D
Wolburg
Hartwig
H
Leithäuser
Frank
F
Schmidt
Volker
V
Deutsch
Urban
U
Wirth
Thomas
T
D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042702:Angiopoietin-2; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2