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Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis. Proc Natl Acad Sci U S A

Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2007; 104(9):3243-8. DOI: 10.1073/pnas.0611510104
Source: PubMed

ABSTRACT 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.

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    • "Many genes misregulated in diseases such as cancer exhibit embryonic lethal phenotypes in knockout mouse models. For example, the disruption of genes involved in angiogenesis such as vascular endothelial growth factor or vascular endothelial receptor tyrosine phosphatase results in vascular defects, leading to embryonic lethality (Carmeliet et al., 1996; Dominguez et al., 2007) and precluding study of the roles of these proteins in tumor angiogenesis. The DHFR-derived DD system may be a suitable alternative for in vivo regulation of proteins that are required during embryonic development. "
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    • "This is in contrast to the large diameter EC-lined cavity that formed when the spheroids were cultured in VEGF-supplemented medium. Based on previous studies in which elevated VEGF levels were shown to promote the formation of large diameter vessels and vascular sinuses via the fusion of small diameter vessels (Drake and Little, 1995; Drake and Fleming, 2000; Argraves et al., 2002; Dor et al., 2002; Dominguez et al., 2007 "
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