Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch
Irene M. Aspalter,Emma Gordon,Alexandre Dubrac,Anan Ragab,Jarek Narloch,Pedro Vizán,Ilse Geudens,Russell T. Collins,Russell T. Collins,Claudio A. Franco,Cristina Abrahams,Gavin Thurston,Marcus Fruttiger,Ian Rosewell,Anne Eichmann,Anne Eichmann,Holger Gerhardt,Holger Gerhardt,Holger Gerhardt +18 more
TLDR
This 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.Abstract:
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.read more
Citations
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Journal ArticleDOI
Mechanisms and regulation of endothelial VEGF receptor signalling
TL;DR: A clear understanding of the tight and multi-level regulation of VEGFR2 signalling is key to successful therapeutic suppression or stimulation of vascular growth.
Journal ArticleDOI
Notch Signaling in Development, Tissue Homeostasis, and Disease
Chris Siebel,Urban Lendahl +1 more
TL;DR: The current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation are discussed.
Journal ArticleDOI
Signaling Receptors for TGF-β Family Members
TL;DR: Transforming growth factor β (TGF-β) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors that are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation.
Journal ArticleDOI
Consensus guidelines for the use and interpretation of angiogenesis assays
Patrycja Nowak-Sliwinska,Kari Alitalo,Elizabeth Allen,Andrey Anisimov,Alfred C. Aplin,Robert Auerbach,Hellmut G. Augustin,Hellmut G. Augustin,David O. Bates,Judy R. van Beijnum,R. Hugh F. Bender,Gabriele Bergers,Gabriele Bergers,Andreas Bikfalvi,Joyce Bischoff,Barbara C. Böck,Barbara C. Böck,Peter C. Brooks,Federico Bussolino,Bertan Cakir,Peter Carmeliet,Daniel Castranova,Anca Maria Cimpean,Ondine Cleaver,George Coukos,George E. Davis,Michele De Palma,Anna Dimberg,Ruud P.M. Dings,Valentin Djonov,Andrew C. Dudley,Neil Dufton,Sarah-Maria Fendt,Napoleone Ferrara,Marcus Fruttiger,Dai Fukumura,Bart Ghesquière,Bart Ghesquière,Yan Gong,Robert J. Griffin,Adrian L. Harris,Christopher C.W. Hughes,Nan W. Hultgren,M. Luisa Iruela-Arispe,Melita Irving,Rakesh K. Jain,Raghu Kalluri,Joanna Kalucka,Robert S. Kerbel,Jan Kitajewski,Ingeborg Klaassen,Hynda K. Kleinmann,Pieter Koolwijk,Elisabeth Kuczynski,Brenda R. Kwak,Koen Marien,Juan M. Melero-Martin,Lance L. Munn,Roberto F. Nicosia,Agnès Noël,Jussi Nurro,Anna-Karin Olsson,Tatiana V. Petrova,Kristian Pietras,Roberto Pili,Jeffrey W. Pollard,Mark J. Post,Paul H.A. Quax,Gabriel A. Rabinovich,Marius Raica,Anna M. Randi,Domenico Ribatti,Curzio Rüegg,Reinier O. Schlingemann,Reinier O. Schlingemann,Stefan Schulte-Merker,Lois E.H. Smith,Jonathan W. Song,Steven A. Stacker,Jimmy Stalin,Amber N. Stratman,Maureen Van de Velde,Victor W.M. van Hinsbergh,Peter B. Vermeulen,Johannes Waltenberger,Brant M. Weinstein,Hong Xin,Bahar Yetkin-Arik,Seppo Ylä-Herttuala,Mervin C. Yoder,Arjan W. Griffioen +90 more
TL;DR: In vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis are described and critical aspects that are relevant for their execution and proper interpretation are highlighted.
Journal ArticleDOI
Vascular heterogeneity and specialization in development and disease.
Michael Potente,Taija Makinen +1 more
TL;DR: How endothelial cells interact with each other and with their tissue environment is illuminated, providing paradigms for vessel type- and organ-specific endothelial differentiation and crucial for understanding how tissues develop and maintain, and how their function becomes abnormal in disease.
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