MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis

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Abstract
During embryogenesis, blood vessels are remodelled in response to blood flow. Nicoli et al. describe a genetic pathway that explains how this mechanosensory stimulus is integrated with early developmental signals to remodel aortic arch vessels in zebrafish. The flow-induced transcription factor klf2a is required for the induction of an endothelial cell-specific microRNA, miR-126, which promotes VEGF signalling and angiogenesis through repressing Spred1, an inhibitor of VEGF signalling. This demonstrates how blood flow modulates endothelial cell-signalling pathways and implicates a microRNA as a central integration point during this process. During embryonic development, blood vessels remodel in response to blood flow. Here, a genetic pathway is described through which this mechanosensory stimulus is integrated with early developmental signals to remodel vessels of the aortic arch in zebrafish. It is found that the flow-induced transcription factor klf2a is required to induce the expression of an endothelial-specific microRNA, activating signalling through the growth factor Vegf. 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 klf2a5,6,7 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.