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PMID:16293765

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Citation

Herrera, VL, Ponce, LR, Bagamasbad, PD, VanPelt, BD, Didishvili, T and Ruiz-Opazo, N (2005) Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis. Physiol. Genomics 23:257-68

Abstract

The dual endothelin-1/angiotensin II receptor (Dear) binds endothelin-1 (ET-1) and angiotensin II (ANG II) with equal affinities in the Dahl S/JRHS rat strain. To elucidate its physiological significance within the context of multiple receptor isoforms and diverse ET-1 and ANG II functions spanning blood pressure regulation, tumor proliferation, and angiogenesis, we characterized mouse Dear and Dear-deficient mice. Unlike null mutant models of ET-1, ANG II, and all other ET-1 and ANG II receptors, Dear(-/-) deficiency results in impaired angiogenesis, dysregulated neuroepithelial development, and embryonic lethality by embryonic day 12.5. Interestingly, mouse Dear does not bind ANG II, similar to Dahl R/JRHS rat Dear, but binds ET-1 and vascular endothelial growth factor (VEGF) signal peptide (VEGFsp) with equal affinities, suggesting a putative novel multifunction for VEGFsp and a parsimonious mechanism for coordination of VEGF-induced and Dear-mediated pathways. Consistent with its developmental angiogenic role, Dear inhibition results in decreased tumor growth in B16-F10 melanoma cell-induced subcutaneous tumor in female Dear(+/-)/C57BL6BC10 mice, but not in males (age 3.5 mo), and in 127Cs radiation-induced orthotopic mammary tumors in Sprague-Dawley female rats (age range 3-6.5 mo). Altogether, the data identify Dear as a new player in angiogenesis during development downstream to, and nonredundant with, VEGF-mediated pathways, as well as a putative modulator of tumor angiogenesis acting within a gender-specific paradigm.

Links

PubMed Online version:10.1152/physiolgenomics.00144.2005

Keywords

Animals; Cloning, Molecular; DNA Primers; Embryonic Development/genetics; Female; Gene Expression Regulation; Genotype; Male; Mice; Mice, Mutant Strains; Neovascularization, Physiologic/genetics; Phenotype; Pregnancy; Receptors, Angiotensin/genetics; Receptors, Endothelin/genetics; Restriction Mapping

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:B2RUM2

acts_upstream_of_or_within

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3623969

P

Seeded From UniProt

complete

MOUSE:B2RUM2

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:32845)

Seeded From UniProt

complete

MOUSE:B2RUM2

enables

GO:0004962: endothelin receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:B2RUM2

enables

GO:0005021: vascular endothelial growth factor-activated receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:B2RUM2

enables

GO:0038085: vascular endothelial growth factor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:Q2QKR2

acts_upstream_of_or_within

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3623969

P

Seeded From UniProt

complete

MOUSE:Q2QKR2

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:32845)

Seeded From UniProt

complete

MOUSE:Q2QKR2

enables

GO:0004962: endothelin receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:Q2QKR2

enables

GO:0005021: vascular endothelial growth factor-activated receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:Q2QKR2

enables

GO:0038085: vascular endothelial growth factor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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