During sprouting angiogenesis, vascular endothelial growth factor (VEGF) activates filopodia formation and the directional migration of an endothelial cell, the tip cell, which takes the lead in forming the new vessel. The tip cell takes with it endothelial trailing stalk cells, which do not make filopodia and form the core of the new vessels. This process also requires inhibition of tip cell behaviour in stalk cells through crosstalk between VEGF and Notch signalling. Lawson and colleagues have delineated a microRNA cascade that modulates tip cell behaviour in zebrafish (Dev. Cell 22, 418–429; 2012).
Using deep sequencing, the authors identify miR-221 as a microRNA specifically induced in endothelial cells at the time of sprouting. They show that following VEGF-C receptor Flt4 loss of function, sprouting angiogenesis is inhibited in embryos injected with miR-221 morpholinos. They find that miR-221 knockdown impairs the migration and proliferation of tip cells, whereas endothelial cells overexpressing miR-221 drive vessel sprouting, resembling Delta-4 (an endothelial Notch ligand) loss-of-function phenotypes. They further show that the excessive sprouting associated with Delta-4 loss of function is suppressed by miR-221 deficiency, and that miR-221 expression is inhibited by Notch signalling. Mechanistically, they find two targets of miR-221 that influence tip cell behaviour: the Cdk inhibitor p27, and the p85α regulatory subunit of the PI(3)K (phosphatidylinositol-3-kinase) complex. Overexpression of both targets negatively influences tip cell behaviour, whereas reducing their levels provides partial rescue of miR-221-associated angiogenic phenotypes. Thus, miR-221 provides a further level of regulation for tip and stalk cell behaviour to ensure correct sprouting angiogenesis.
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