Abstract
The mature circulatory system is comprised of two parallel, yet distinct, vascular networks that carry blood to and from the heart. Studies have suggested that endothelial tubes are specified as arteries and veins at the earliest stages of angiogenesis, before the onset of circulation1,2,3,4. To understand the molecular basis for arterial-venous identity, we have focused our studies on a human vascular dysplasia, hereditary haemorrhagic telangiectasia (HHT), wherein arterial and venous beds fail to remain distinct. Genetic studies have demonstrated that HHT can be caused by loss-of-function mutations in the gene encoding activin receptor-like kinase-1 (ACVRL1; ref. 5). ACVRL1 encodes a type I receptor for the TGF-β superfamily of growth factors6,7,8. At the earliest stage of vascular development, mice lacking Acvrl1 develop large shunts between arteries and veins, downregulate arterial Efnb2 and fail to confine intravascular haematopoiesis to arteries. These mice die by mid-gestation with severe arteriovenous malformations resulting from fusion of major arteries and veins. The early loss of anatomical, molecular and functional distinctions between arteries and veins indicates that Acvrl1 is required for developing distinct arterial and venous vascular beds.
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References
Gale, N.W. & Yancopoulos, G.D. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 13, 1055–1066 (1999).
Adams, R.H. et al. Roles of ephrin B ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 13, 295–306 (1999).
Wang, H.U., Chen, Z.F. & Anderson, D.J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).
Gerety, S.S., Wang, H.U., Chen, Z.F. & Anderson, D.J. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol. Cell 4, 403–414 (1999).
Johnson, D.W. et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nature Genet. 13, 189–195 (1996).
ten Dijke, P. et al. Characterization of type I receptors for transforming growth factor-β and activin. Science 264, 101–104 (1994).
ten Dijke, P. et al. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 10, 2879–2887 (1993).
Attisano, L. & Wrana, J.L. Signal transduction by members of the transforming growth factor-β superfamily. Cytokine Growth Factor Rev. 7, 327–339 (1996).
Vecchi, A. et al. Monoclonal antibodies specific for endothelial cells of mouse blood vessels. Their application in the identification of adult and embryonic endothelium. Eur. J. Cell Biol. 63, 247–254 (1994).
Gadson, P.F., Rossignol, C., McCoy, J. & Rosenquist, T.H. Expression of elastin, smooth muscle α actin and c-Jun as a function of the embryonic lineage of vascular smooth muscle cells. In Vitro Cell. Dev. Biol. 29A, 773–781 (1993).
Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).
Dumont, D.J. et al. Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev. Dyn. 203, 80–92 (1995).
Garcia-Porrero, J.A., Godin, I.E. & Dieterlen-Lievre, F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat. Embryol. (Berl.) 192, 425–435 (1995).
Manaia, A. et al. Lmo2 and GATA-3 associated expression in intraembryonic hemogenic sites. Development 127, 643–653 (2000).
Jeffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998).
Dieterlen-Lievre, F. & Martin, C. Diffuse intraembryonic hematopoiesis in normal and chimeric avian development. Dev. Biol . 88, 180–191 (1981).
Tavian, M. et al. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87, 67–72 (1996).
Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).
Jaffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998).
Pepper, M.S. Transforming growth factor-β: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 8, 21–43 (1997).
Pepper, M.S., Mandriota, S., Vassalli, J.-D. & Orci, L. Angiogenesis regulating cytokines: activities and interactions. Curr. Top. Microbiol. Immunol. 213, 31–67 (1996).
Li, D.Y. et al. Elastin is an essential determinant of arterial morphogenesis. Nature 393, 276–280 (1998).
Flamme, I. & Risau, W. Induction of vasculogenesis and hematopoiesis. Development 116, 435–439 (1992).
Wilkinson, D.G. In Situ Hybridization (IRL Press, Oxford, 1992).
Hogan, B., Constantin, F. & Lacy, E. Manipulating The Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Press, Plainview, 1986).
Srivastava, D. et al. Regulation of cardiac mesodermal and neural crest development by the HLH transcription factor, dHAND. Nature Genet. 16, 154–160 (1997).
St.-Jacques, S., Cymerman, U., Pece, N. & Letarte, M. Molecular characterization and in situ localization of murine endoglin reveal that it is a transforming growth factor-β binding protein of endothelial and stromal cells. Endocrinology 134, 2645–2657 (1994).
Acknowledgements
We thank M. Keating and his laboratory for scientific, technical and editorial expertise; B. Boak, D. Taylor and J.R. Redstone for technical assistance; J. Miano, C. Mummery, R. Klein and D. Anderson for probes; E.C. Davis for electron microscopy; R. Wesselschimdt for ES cells and chimaeric mice; S. Odelberg, M. Sanguinetti and K. Thomas for comments; and D. Lim for assistance with figures. This work was supported by the NIH, American Heart Association, Rockefeller Brothers Fund and the University of Utah.
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Urness, L., Sorensen, L. & Li, D. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 26, 328–331 (2000). https://doi.org/10.1038/81634
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DOI: https://doi.org/10.1038/81634
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