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Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch.
journal contributionposted on 2023-08-16, 12:51 authored by Irene Maria Aspalter, Emma Gordon, Alexandre Dubrac, Anan Ragab, Jarek Narloch, Pedro Vizán, Ilse Geudens, Russell Thomas Collins, Claudio Areias Franco, Cristina Luna Abrahams, Gavin Thurston, Marcus Fruttiger, Ian Rosewell, Anne Eichmann, Holger Gerhardt
Sprouting angiogenesis drives blood vessel growth in healthy and diseased tissues. Vegf and Dll4/Notch signalling cooperate in a negative feedback loop that specifies endothelial tip and stalk cells to ensure adequate vessel branching and function. Current concepts posit that endothelial cells default to the tip-cell phenotype when Notch is inactive. Here we identify instead that the stalk-cell phenotype needs to be actively repressed to allow tip-cell formation. We show this is a key endothelial function of neuropilin-1 (Nrp1), which suppresses the stalk-cell phenotype by limiting Smad2/3 activation through Alk1 and Alk5. Notch downregulates Nrp1, thus relieving the inhibition of Alk1 and Alk5, thereby driving stalk-cell behaviour. Conceptually, our work shows that the heterogeneity between neighbouring endothelial cells established by the lateral feedback loop of Dll4/Notch utilizes Nrp1 levels as the pivot, which in turn establishes differential responsiveness to TGF-β/BMP signalling.
Activin Receptors, Type IActivin Receptors, Type IIAnimalsEndothelium, VascularGrowth Differentiation Factor 2Human Umbilical Vein Endothelial CellsHumansIntracellular Signaling Peptides and ProteinsMembrane ProteinsMiceNeuropilin-1PhenotypeProtein Serine-Threonine KinasesReceptor, Transforming Growth Factor-beta Type IReceptors, NotchReceptors, Transforming Growth Factor betaSmad2 ProteinSmad3 ProteinBRF