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Regulation of angiogenesis by a non-canonical Wnt–Flt1 pathway in myeloid cells

Nature volume 474, pages 511–515 (2011)Cite this article

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Abstract

Myeloid cells are a feature of most tissues. Here we show that during development, retinal myeloid cells (RMCs) produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally1, somatic deletion in RMCs of the Wnt ligand transporter Wntless2,3 results in increased angiogenesis in the deeper layers. We also show that mutation of Wnt5a and Wnt11 results in increased angiogenesis and that these ligands elicit RMC responses via a non-canonical Wnt pathway. Using cultured myeloid-like cells and RMC somatic deletion of Flt1, we show that an effector of Wnt-dependent suppression of angiogenesis by RMCs is Flt1, a naturally occurring inhibitor of vascular endothelial growth factor (VEGF)4,5,6. These findings indicate that resident myeloid cells can use a non-canonical, Wnt–Flt1 pathway to suppress angiogenic branching.

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Figure 1: RMCs interact with VECs and express Wnt components.
Figure 2: RMC Wls is required for suppression of deep angiogenic branching.
Figure 3: Angiogenic suppression by RMCs is a non-canonical Wnt response.
Figure 4: Flt1 expression in myeloid cells is regulated by a Wnt pathway.

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Acknowledgements

We thank P. Speeg for technical assistance and A. P. McMahon for the Wnt11 mice. This work was supported by the NIH (J.A.S., M.W-K., J.W.P., J.D.M., T.Y., B.O.W., R.A.L.) by the HHMI (J.D.M.) and Cancer Research UK (H.G.).

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Authors and Affiliations

  1. Divisions of Pediatric Ophthalmology and Developmental Biology, The Visual Systems Group, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA,

    James A. Stefater III, Sujata Rao, April C. Carpenter, Jieqing Fan & Richard A. Lang

  2. Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio 45229, USA,

    James A. Stefater III, Sujata Rao, April C. Carpenter, Jieqing Fan & Richard A. Lang

  3. Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA,

    Ian Lewkowich & Marsha Wills-Karp

  4. Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2 3PX, UK ,

    Giovanni Mariggi & Holger Gerhardt

  5. Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Ohio 45229, USA

    Adam R. Burr & Jeffery D. Molkentin

  6. Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, Maryland 21701, USA ,

    Rieko Ajima & Terry Yamaguchi

  7. Howard Hughes Medical Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Ohio 45229, USA

    Jeffery D. Molkentin

  8. Center for Skeletal Disease Research, Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, Michigan 49503, USA ,

    Bart O. Williams

  9. Albert Einstein College of Medicine of Yeshiva University, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Bronx, New York 10461, USA ,

    Jeffrey W. Pollard

  10. Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA ,

    Napoleone Ferrara

  11. Consultant Group Leader, Vascular Patterning Laboratory, Vesalius Research Center, VIB, Campus Gasthuisberg, B-3000 Leuven, Belgium ,

    Holger Gerhardt

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  1. James A. Stefater III
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Contributions

R.A.L provided project leadership and wrote the manuscript with J.A.S. J.A.S., I.L., S.R., H.G., and R.A.L. designed the experiments. J.A.S, I.L., S.R., G.M., A.C.C., A.R.B., J.F., and R.A. performed the experiments. S.R., J.W.P., T.Y., N.F. and B.O.W developed critical reagents. Experimental supervision and helpful discussions were provided by M.W-K., J.D.M., S.R., J.W.P., and H.G.

Corresponding author

Correspondence to Richard A. Lang.

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Competing interests

[Competing interest: N.F. is an employee of Genentech Inc. The authors declare no other potential conflicts of interest.]

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Stefater III, J., Lewkowich, I., Rao, S. et al. Regulation of angiogenesis by a non-canonical Wnt–Flt1 pathway in myeloid cells. Nature 474, 511–515 (2011). https://doi.org/10.1038/nature10085

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