Letter

Nature 464, 1196-1200 (22 April 2010) | doi:10.1038/nature08889; Received 13 July 2009; Accepted 10 February 2010; Published online 4 April 2010

There is a Corrigendum (16 September 2010) associated with this document.

MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis

Stefania Nicoli1, Clive Standley2, Paul Walker3, Adam Hurlstone3, Kevin E. Fogarty2 & Nathan D. Lawson1

  1. Program in Gene Function and Expression,
  2. Biomedical Imaging Group, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
  3. Molecular Cancer Studies Group, Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK

Correspondence to: Nathan D. Lawson1 Correspondence and requests for materials should be addressed to N.D.L. (Email: nathan.lawson@umassmed.edu).

Within the circulatory system, blood flow regulates vascular remodelling1, stimulates blood stem cell formation2, and has a role in the pathology of vascular disease3. During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act before circulation4. Subsequently, endothelial cells must incorporate the mechanosensory stimulus of blood flow with these early signals to shape the embryonic vascular system4. However, few details are known about how these signals are integrated during development. To investigate this process, we focused on the aortic arch (AA) blood vessels, which are known to remodel in response to blood flow1. By using two-photon imaging of live zebrafish embryos, we observe that flow is essential for angiogenesis during AA development. We further find that angiogenic sprouting of AA vessels requires a flow-induced genetic pathway in which the mechano-sensitive zinc finger transcription factor klf2a 5, 6, 7 induces expression of an endothelial-specific microRNA, mir-126, to activate Vegf signalling. Taken together, our work describes a novel genetic mechanism in which a microRNA facilitates integration of a physiological stimulus with growth factor signalling in endothelial cells to guide angiogenesis.

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