Vegfa signaling regulates diverse artery/vein formation in vertebrate vasculatures

Vascular endothelial growth factor A（Vegfa） signaling regulates vascular development during embryogenesis and organ formation.However,the signaling mechanisms that govern the formation of various arteries/veins in various tissues are incompletely understood.In this study,we utilized transcription activator-like effector nuclease（TALEN） to generate zebrafish vegfaa mutants.vegfaa^-/- embryos are embryonic lethal,and display a complete loss of the dorsal aorta（DA） and expansion of the cardinal vein.Activation of Vegfa signaling expands the arterial cell population at the expense of venous cells during vasculogenesis of the axial vessels in the trunk.Vegfa signaling regulates endothelial cell（EC） proliferation after arterial-venous specification.Vegfa deficiency and overexpression inhibit the formation of tip cell filopodia and interfere with the pathfinding of intersegmental vessels（ISVs）.In the head vasculature,vegfaa^-/- causes loss of a pair of mesencephalic veins（MsVs） and central arteries（CtAs）,both of which usually dvelop via sprouting angiogenesis.Our results indicate that Vegfa signaling induces the formation of the DA at the expense of the cardinal vein during the trunk vasculogenesis,and that Vegfa is required for the angiogenic formation of MsVs and CtAs in the brain.These findings suggest that Vegfa signaling governs the formation of diverse arteries/veins by distinct cellular mechanisms in vertebrate vasculatures.

Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration

Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.