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Arteriovenous malformations in mice lacking activin receptor-like kinase-1

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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Figure 1: Targeted inactivation of mouse Acvrl1 results in failed extra-embryonic vascular development.
Figure 2: Acvrl1−/− embryos develop A-V shunts early in vascular development.
Figure 3: Acvrl1−/− embryos have defective endothelial remodelling and poor VSMC formation.
Figure 4: Arterial-specific Efnb2 is downregulated in Acvrl1−/− embryos.
Figure 5: Ectopic development of intra-embryonic haematopoietic clusters in Acvrl1−/− venous endothelium.
Figure 6: Proposed model for the hierarchy of gene expression that regulates the early development of arterial and venous vascular beds.

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References

  1. 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).

    Article  CAS  Google Scholar 

  2. 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).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. ten Dijke, P. et al. Characterization of type I receptors for transforming growth factor-β and activin. Science 264, 101–104 (1994).

    Article  CAS  Google Scholar 

  7. 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).

    Google Scholar 

  8. Attisano, L. & Wrana, J.L. Signal transduction by members of the transforming growth factor-β superfamily. Cytokine Growth Factor Rev. 7, 327–339 (1996).

    Article  CAS  Google Scholar 

  9. 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).

    CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Manaia, A. et al. Lmo2 and GATA-3 associated expression in intraembryonic hemogenic sites. Development 127, 643–653 (2000).

    CAS  Google Scholar 

  15. Jeffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998).

    Google Scholar 

  16. Dieterlen-Lievre, F. & Martin, C. Diffuse intraembryonic hematopoiesis in normal and chimeric avian development. Dev. Biol . 88, 180–191 (1981).

    Article  CAS  Google Scholar 

  17. Tavian, M. et al. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87, 67–72 (1996).

    CAS  Google Scholar 

  18. Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).

    Article  CAS  Google Scholar 

  19. Jaffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998).

    CAS  Google Scholar 

  20. Pepper, M.S. Transforming growth factor-β: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 8, 21–43 (1997).

    Article  CAS  Google Scholar 

  21. Pepper, M.S., Mandriota, S., Vassalli, J.-D. & Orci, L. Angiogenesis regulating cytokines: activities and interactions. Curr. Top. Microbiol. Immunol. 213, 31–67 (1996).

    CAS  Google Scholar 

  22. Li, D.Y. et al. Elastin is an essential determinant of arterial morphogenesis. Nature 393, 276–280 (1998).

    Article  CAS  Google Scholar 

  23. Flamme, I. & Risau, W. Induction of vasculogenesis and hematopoiesis. Development 116, 435–439 (1992).

    CAS  Google Scholar 

  24. Wilkinson, D.G. In Situ Hybridization (IRL Press, Oxford, 1992).

    Google Scholar 

  25. Hogan, B., Constantin, F. & Lacy, E. Manipulating The Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Press, Plainview, 1986).

    Google Scholar 

  26. Srivastava, D. et al. Regulation of cardiac mesodermal and neural crest development by the HLH transcription factor, dHAND. Nature Genet. 16, 154–160 (1997).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

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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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