Endoglin is required in Pax3-derived cells for embryonic blood vessel formation.
Mutations in endoglin, a TGFβ/BMP coreceptor, are causal for hereditary hemorrhagic telangiectasia (HHT). Endoglin-null (Eng-/-) mouse embryos die at embryonic day (E)10.5-11.5 due to defects in angiogenesis. In part, this is due to an absence of vascular smooth muscle cell differentiation and vessel investment. Prior studies from our lab and others have shown the importance of endoglin expression in embryonic development in both endothelial cells and neural crest stem cells. These studies support the hypothesis that endoglin may play cell-autonomous roles in endothelial and vascular smooth muscle cell precursors. However, the requirement for endoglin in vascular cell precursors remains poorly defined. Our objective was to specifically delete endoglin in neural crest- and somite-derived Pax3-positive vascular precursors to understand the impact on somite progenitor cell contribution to embryonic vascular development. Pax3Cre mice were crossed with Eng+/- mice to obtain compound mutant Pax3(Cre/+);Eng+/- mice. These mice were then crossed with homozygous endoglin LoxP-mutated (Eng(LoxP/LoxP)) mice to conditionally delete the endoglin gene in specific lineages that contribute to endothelial and smooth muscle constituents of developing embryonic vessels. Pax3(Cre/+);Eng(LoxP/)(-) mice showed a variety of vascular defects at E10.5, and none of these mice survived past E12.5. Embryos analyzed at E10.5 showed malformations suggestive of misdirection of the intersomitic vessels. The dorsal aorta showed significant dilation with associated vascular smooth muscle cells exhibiting disorganization and enhanced expression of smooth muscle differentiation proteins, including smooth muscle actin. These results demonstrate a requirement for endoglin in descendants of Pax3-expressing vascular cell precursors, and thus provides new insight into the cellular basis underlying adult vascular diseases such as HHT.
Maine Medical Center Research Institute, Scarborough, ME, United States; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, United States; The Jackson Laboratory, Bar Harbor, ME, United States.
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Young
Maine Medical Center Research Institute, Scarborough, ME, United States.
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Krebs
Maine Medical Center Research Institute, Scarborough, ME, United States.
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Tweedie
Maine Medical Center Research Institute, Scarborough, ME, United States.
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Conley
Maine Medical Center Research Institute, Scarborough, ME, United States; Champions Oncology, Baltimore, MD, United States.
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Mancini
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
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Arthur
Maine Medical Center Research Institute, Scarborough, ME, United States; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, United States.
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Liaw
Maine Medical Center Research Institute, Scarborough, ME, United States; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, United States.
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Gridley
Maine Medical Center Research Institute, Scarborough, ME, United States; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, United States. Electronic address: varyc@mmc.org.
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D000199:Actins / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001011:Aorta / Q000196:embryology / Q000473:pathology; D001808:Blood Vessels / Q000196:embryology* / Q000378:metabolism*; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018919:Neovascularization, Physiologic; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D010641:Phenotype; D011995:Recombination, Genetic / Q000235:genetics; D019170:Somites / Q000098:blood supply; D013194:Staining and Labeling
D000199:Actins; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; C068686:Pax3 protein, mouse; C045073:Cre recombinase; D019426:Integrases
Dorsal aorta; Endoglin; HHT; Intersomitic; Pax3; Vascular malformation