Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis.
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.
Herrera
Victoria L M
VL
Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
Ponce
Lorenz R B
LR
Bagamasbad
Pia D
PD
VanPelt
Benjamin D
BD
Didishvili
Tamara
T
Ruiz-Opazo
Nelson
N
D000818:Animals; D003001:Cloning, Molecular; D017931:DNA Primers; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy; D011945:Receptors, Angiotensin / Q000235:genetics*; D017466:Receptors, Endothelin / Q000235:genetics*; D015183:Restriction Mapping
D017931:DNA Primers; C510877:Dear1 protein, mouse; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin