MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis.
Within the circulatory system, blood flow regulates vascular remodelling, stimulates blood stem cell formation, and has a role in the pathology of vascular disease. During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act before circulation. Subsequently, endothelial cells must incorporate the mechanosensory stimulus of blood flow with these early signals to shape the embryonic vascular system. 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 flow. 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 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.
Nicoli
Stefania
S
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Standley
Clive
C
Walker
Paul
P
Hurlstone
Adam
A
Fogarty
Kevin E
KE
Lawson
Nathan D
ND
D000818:Animals; D001013:Aorta, Thoracic / Q000196:embryology*; D042783:Endothelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006439:Hemodynamics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic; D012039:Regional Blood Flow / Q000502:physiology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015027:Zebrafish / Q000097:blood / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; C436494:Klf2a protein, zebrafish; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D035683:MicroRNAs; C549766:Mirn126 microRNA, zebrafish; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; C549767:spred1 protein, Danio rerio