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: 9.67). 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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    • "Other mutation players within the TEK pathway, especially those proximal to the receptor, could also be expected to yield similar, specific phenotypes. These include TIE-1, which can heterodimerise with TEK [31, 32]; the Ang ligands [29–35]; and the vascular endothelial protein tyrosine phosphatase (VE-PTP), which can specifically regulate TEK activation [36, 37]. "
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    ABSTRACT: Background. Venous malformations (VM) result from an error in vascular morphogenesis. The first gene suspected in their development is the TEK gene (tyrosine kinase, endothelial). Mutations of this gene have been identified in several Belgian families with a dominant form of the disease. Therefore, we investigated whether mutations in this TEK gene could explain the MV development in patients of families from Tlemcen region (north-western Algeria). Methods. Genomic DNA was extracted from leucocytes of ten patients. The search for mutations in all the 23 exons and in the 5' and 3' intronic sequences flanking the TEK gene was performed using PCR amplification and direct sequencing of amplified genomic DNA. Additionally, a search for somatic mutations of the gene TEK was performed on a biopsy of the venous malformation from one of the ten eligible patients. Results. The sequencing of the 23 exons of the TEK gene revealed neither germinal mutation in our ten patients nor somatic mutation in the tissue of the biopsy. Conclusion. The absence of mutation in the TEK gene in the population studied suggests that the TEK gene is not necessarily involved in the onset of VM; its association with these malformations may differ from one population to another.
    12/2013; 2013(16):784789. DOI:10.1155/2013/784789
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    • "Prdm6 deficiency therefore apparently affects aspects of angiogenesis. Embryonic lethal phenotypes involving intact vasculogenesis, but impaired angiogenesis have been described for mice that are deficient in a variety of genes, such as Fzd5 [29], Notch1 [30,31], Jagged1 [32], Hey1/Hey2 [33], Smoothened [34], Eph-B4 and Ephrin-B2 [35], Angiopoietin [36], Tie2 [37], Smad5 [38], Quaking [39], HIF2alpha- [40], VE-PTP [41], SCL/Tal-1 [42], and PI3K p110-α [43]. Inactivation of those key regulators of angiogenesis results in embryonic death latest by E11.0. "
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    ABSTRACT: Members of the PRDM protein family have been shown to play important roles during embryonic development. Previous in vitro and in situ analyses indicated a function of Prdm6 in cells of the vascular system. To reveal physiological functions of Prdm6, we generated conditional Prdm6-deficient mice. Complete deletion of Prdm6 results in embryonic lethality due to cardiovascular defects associated with aberrations in vascular patterning. However, smooth muscle cells could be regularly differentiated from Prdm6-deficient embryonic stem cells and vascular smooth muscle cells were present and proliferated normally in Prdm6-deficient embryos. Conditional deletion of Prdm6 in the smooth muscle cell lineage using a SM22-Cre driver line resulted in perinatal lethality due to hemorrhage in the lungs. We thus identified Prdm6 as a factor that is essential for the physiological control of cardiovascular development.
    PLoS ONE 11/2013; 8(11):e81833. DOI:10.1371/journal.pone.0081833 · 3.23 Impact Factor
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    • "The main vascular defects observed were in the intersomitic vessels of the tail (71%; n = 56), which appeared truncated or with anomalous branching (Figure S2 B). These data are in agreement with the Ve-ptp mutant and null mice phenotypes, confirming in zebrafish the conservation of Ve-ptp function in angiogenic and remodeling processes [18], [19]. "
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    ABSTRACT: Endothelial cell junctions control blood vessel permeability. Altered permeability can be associated with vascular fragility that leads to vessel weakness and haemorrhage formation. In vivo studies on the function of genes involved in the maintenance of vascular integrity are essential to better understand the molecular basis of diseases linked to permeability defects. Ve-ptp (Vascular Endothelial-Protein Tyrosine Phosphatase) is a transmembrane protein present at endothelial adherens junctions (AJs). We investigated the role of Ve-ptp in AJ maturation/stability and in the modulation of endothelial permeability using zebrafish (Danio rerio). Whole-mount in situ hybridizations revealed zve-ptp expression exclusively in the developing vascular system. Generation of altered zve-ptp transcripts, induced separately by two different splicing morpholinos, resulted in permeability defects closely linked to vascular wall fragility. The ultrastructural analysis revealed a statistically significant reduction of junction complexes and the presence of immature AJs in zve-ptp morphants but not in control embryos. Here we show the first in vivo evidence of a potentially critical role played by Ve-ptp in AJ maturation, an important event for permeability modulation and for the development of a functional vascular system.
    PLoS ONE 12/2012; 7(12):e51245. DOI:10.1371/journal.pone.0051245 · 3.23 Impact Factor
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