TY - JOUR
T1 - Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch
AU - Aspalter, Irene Maria
AU - Gordon, Emma
AU - Dubrac, Alexandre
AU - Ragab, Anan
AU - Narloch, Jarek
AU - Vizán, Pedro
AU - Geudens, Ilse
AU - Collins, Russell Thomas
AU - Franco, Claudio Areias
AU - Abrahams, Cristina Luna
AU - Thurston, Gavin
AU - Fruttiger, Marcus
AU - Rosewell, Ian
AU - Eichmann, Anne
AU - Gerhardt, Holger
N1 - Funding Information:
We are grateful to Dr Guido Serini for provision of Nrp1 expression constructs. We thank Dr Daniel Greif and Dr Teodelinda Mirabella (Yale University) for providing Alk5 floxed mice. We thank Dr Caroline Hill (London Research Institute, CRUK) for her invaluable scientific input and Michael Simons for critical reading of the manuscript. Furthermore, we thank Mary Ann Haskings (Transgenic Services, London Research Institute—Clare Hall Laboratories) for her help in generating chimeric mice. I.M.A. is a recipient of a DOC-fFORTE fellowship of the Austrian Academy of Sciences at the London Research Institute—Cancer Research UK. C.A.F. is supported by a EU FP7 Marie Curie Post-doctoral Fellowship. This work was supported by Cancer Research UK (H.G.), the EMBO Young Investigator Programme (H.G.), the Lister Institute of Preventive Medicine (H.G.), the ERC starting grant Reshape (311719) (H.G.), the Leducq Transatlantic Network ARTEMIS (H.G. and A.E.), NIH R01 HL 111504-02 (A.E.) and Thome Memorial Foundation (A.E.).
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/6/17
Y1 - 2015/6/17
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84934981272
U2 - 10.1038/ncomms8264
DO - 10.1038/ncomms8264
M3 - Article
C2 - 26081042
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 7264
ER -