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Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein

Abstract

Angiogenesis, the formation of new blood vessels from pre-existing vessels, is critical to most physiological processes and many pathological conditions. During zebrafish development, angiogenesis expands the axial vessels into a complex vascular network that is necessary for efficient oxygen delivery. Although the dorsal aorta and the axial vein are spatially juxtaposed, the initial angiogenic sprouts from these vessels extend in opposite directions, indicating that distinct cues may regulate angiogenesis of the axial vessels. We found that angiogenic sprouts from the dorsal aorta are dependent on vascular endothelial growth factor A (Vegf-A) signalling, and do not respond to bone morphogenetic protein (Bmp) signals. In contrast, sprouts from the axial vein are regulated by Bmp signalling independently of Vegf-A signals, indicating that Bmp is a vein-specific angiogenic cue during early vascular development. Our results support a paradigm whereby different signals regulate distinct programmes of sprouting angiogenesis from the axial vein and dorsal aorta, and indicate that signalling heterogeneity contributes to the complexity of vascular networks.

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Figure 1: The axial vein forms angiogenic sprouts despite loss of Vegf receptor activity, and expresses Bmp pathway components.
Figure 2: Bmp signalling is necessary and sufficient for sprouting from the axial vein.
Figure 3: Angiogenesis from the axial vein requires bmpr2a and bmpr2b and involves endothelial cell autonomous activation of Bmp signalling.
Figure 4: Activation of R-Smad and Erk mediates Bmp-induced angiogenesis.
Figure 5: Bmp signalling regulates axial vein angiogenesis independently of Vegf receptor activity.

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Acknowledgements

The authors thank E. Flynn for excellent fish care; the members of the Jin and Bautch laboratories for discussions; the UNC Histology Facility; Michael Hooker Microscopy Facility; W. Comb and M. Aleman for technical assistance; and M. Hammerschmidt and N. Chi for providing transgenic lines, and C-B. Chien for the kdrl 5′ entry gateway vector. The authors also thank F. Conlon, M. Majesky, C. Patterson and J. Rawls for discussion and critical reading of the manuscript. This study was supported by grants from the NIH to S-W.J. (HL090960) and V.L.B. (HL43174 and HL86564), and the UNC Integrative Vascular Biology Training Grant (T32HL69768) and an American Heart Association Pre-doctoral Fellowship to D.M.W.

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Authors

Contributions

D.M.W., V.L.B. and S-W.J. designed the experiments, D.M.W. carried out the experiments, J-D.K. helped with in situ hybridization, J.H. and C.C.H. provided key reagents and D.M.W., V.L.B. and S-W.J. wrote the manuscript.

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Correspondence to Victoria L. Bautch or Suk-Won Jin.

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Wiley, D., Kim, JD., Hao, J. et al. Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat Cell Biol 13, 686–692 (2011). https://doi.org/10.1038/ncb2232

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