VE-PTP controls blood vessel development by balancing Tie-2 activity.
Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an endothelial-specific receptor-type tyrosine phosphatase that associates with Tie-2 and VE-cadherin. VE-PTP gene disruption leads to embryonic lethality, vascular remodeling defects, and enlargement of vascular structures in extraembryonic tissues. We show here that antibodies against the extracellular part of VE-PTP mimic the effects of VE-PTP gene disruption exemplified by vessel enlargement in allantois explants. These effects require the presence of the angiopoietin receptor Tie-2. Analyzing the mechanism we found that anti-VE-PTP antibodies trigger endocytosis and selectively affect Tie-2-associated, but not VE-cadherin-associated VE-PTP. Dissociation of VE-PTP triggers the activation of Tie-2, leading to enhanced endothelial cell proliferation and enlargement of vascular structures through activation of Erk1/2. Importantly, the antibody effect on vessel enlargement is also observed in newborn mice. We conclude that VE-PTP is required to balance Tie-2 activity and endothelial cell proliferation, thereby controlling blood vessel development and vessel size.
Winderlich
Mark
M
Max-Planck-Institute of Molecular Biomedicine, D-48149 Münster, Germany.
Keller
Linda
L
Cagna
Giuseppe
G
Broermann
Andre
A
Kamenyeva
Olena
O
Kiefer
Friedemann
F
Deutsch
Urban
U
Nottebaum
Astrid F
AF
Vestweber
Dietmar
D
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001808:Blood Vessels / Q000254:growth & development*; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000098:blood supply; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000502:physiology*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D048052:Mitogen-Activated Protein Kinase 3; D042787:Receptor, TIE-2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D000099152:Cadherin 5