Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis.
Development of the vascular system depends on the highly coordinated actions of a variety of angiogenic regulators. Several of these regulators are members of the tyrosine kinase superfamily, including VEGF receptors and angiopoietin receptors, Tie1 and Tie2. Tyrosine kinase signaling is counter-regulated by the activity of tyrosine phosphatases, including vascular endothelial protein tyrosine phosphatase (VE-PTP), which has previously been shown to modulate Tie2 activity. We generated mice in which VE-PTP is replaced with a reporter gene. We confirm that VE-PTP is expressed in endothelium and also show that VE-PTP is highly expressed in the developing outflow tract of the heart and later is expressed in developing heart valves. Vasculogenesis occurs normally in mice lacking VE-PTP; however, angiogenesis is abnormal. Angiogenic defects in VE-PTP-null mice were most pronounced in the yolk sac and include a complete failure to elaborate the primitive vascular scaffold into higher-order branched arteries, veins, and capillaries. VE-PTP continues to be expressed into adulthood in the vasculature and heart valves, suggesting later roles in vascular development or homeostasis. VE-PTP is also expressed in the vasculature of growing tumors, suggesting that VE-PTP may be a new potential target for angiogenic therapies.
Dominguez
Melissa G
MG
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Hughes
Virginia C
VC
Pan
Li
L
Simmons
Mary
M
Daly
Christopher
C
Anderson
Keith
K
Noguera-Troise
Irene
I
Murphy
Andrew J
AJ
Valenzuela
David M
DM
Davis
Samuel
S
Thurston
Gavin
G
Yancopoulos
George D
GD
Gale
Nicholas W
NW
D000818:Animals; D001808:Blood Vessels / Q000196:embryology* / Q000378:metabolism; D017931:DNA Primers; D042783:Endothelial Cells / Q000378:metabolism*; D017353:Gene Deletion; D018390:Gene Targeting; D006351:Heart Valves / Q000378:metabolism; D007763:Lac Operon; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics* / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015017:Yolk Sac / Q000098:blood supply* / Q000378:metabolism
D017931:DNA Primers; D017027:Protein Tyrosine Phosphatases; C516887:Ptprb protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3