Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis

• Published in: Physiological genomics 2005-11, Vol.23 (3), p.257-268
• Main Authors: Herrera, Victoria L. M, Ponce, Lorenz R. B, Bagamasbad, Pia D, VanPelt, Benjamin D, Didishvili, Tamara, Ruiz-Opazo, Nelson
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00144.2005

Section of Molecular Medicine, Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 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/JR HS 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/JR HS 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 +/– /C57BL6 BC10 mice, but not in males (age 3.5 mo), and in 127 Cs 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. endothelin-1 receptor; VEGF signal peptide; vascular development; neuroepithelial development; cardiac development