Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis
| Autor: | Pia Bagamasbad, Victoria L. M. Herrera, Lorenz R. B. Ponce, Nelson Ruiz-Opazo, Benjamin D. VanPelt, Tamara Didishvili |
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| Rok vydání: | 2005 |
| Předmět: |
Male
medicine.medical_specialty Angiotensin receptor Genotype Physiology Angiogenesis Restriction Mapping Embryonic Development Neovascularization Physiologic Biology Mice Endothelin-1 Receptor Pregnancy Internal medicine Genetics medicine Deficient mouse Animals Cloning Molecular Gene DNA Primers Receptors Angiotensin Receptors Endothelin Rat strain Embryonic stem cell Angiotensin II Mice Mutant Strains Endocrinology Phenotype Gene Expression Regulation Female |
| Zdroj: | Physiological genomics. 23(3) |
| ISSN: | 1531-2267 |
| Popis: | 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/JRHSrat 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/JRHSrat 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+/−/C57BL6BC10mice, but not in males (age 3.5 mo), and in127Cs 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. |
| Databáze: | OpenAIRE |
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