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Angiogenesis Signalling cartoon

a General signalling pathways that control endothelial cell behaviour

Mammalian vascular endothelial growth factors (VEGFs) bind homodimers and heterodimers of three VEGF receptors (VEGFRs). Signalling via VEGFR2, VEGFR3 or VEGFR2 VEGFR3 heterodimers is pro-angiogenic. Proteolytic processing of VEGFC and VEGFD is required to permit their interaction with VEGFR2. VEGFA binding to VEGFR1 and the secreted VEGFR1 extracellular domain (soluble VEGFR1 (sVEGFR1)) acts as a sink for VEGFA that limits its availability to activate VEGFR2. The interaction of TIE2 receptor with matrix-associated angiopoietin 1 (ANG1) at EC–extracellular matrix (ECM) junctions induces migration125. By contrast, at EC–EC junctions ANG1–TIE2 interactions promote quiescence upon trans-complex formation with TIE2 on adjacent cells. These complexes include vascular endothelial protein Tyr phosphatase (VE-PTP; also known as PTPRB) and activate distinct signalling pathways from those at cell–matrix contacts125. ANG2 antagonizes ANG1 activity on TIE2 to destabilize vessels and aid angiogenic remodelling. Homophilic VE-cadherin interactions maintain EC–EC junctions. Delta-like 4 (DLL4)-mediated activation of Notch receptors represses angiogenic cell behaviour and promotes vessel stability upon the proteolytic release of the Notch intracellular domain (NICD). In certain contexts, Jagged 1 competes with DLL4 for Notch to decrease DLL4–Notch-mediated signalling. endothelial cell (EC)

b Known axon guidance receptors expressed in endothelial cells

Roundabout homologue 4 (ROBO4)–uncoordinated 5 homologue B (UNC5B) interactions promote UNC5B-mediated inhibition of VEGFR signalling, block angiogenesis and maintain vessel integrity. Activation of ROBO4 by Slit 2 may also block VEGFR signalling but is controversial. Activation of UNC5B by netrins may also disrupt angiogenesis. Secreted class III semaphorins (such as semaphorin 3E (SEMA3E)) promote EC repulsion to perturb angiogenesis upon binding their receptor, plexin D1. By contrast, neuropilin 1 (NRP1) or NRP2 augment angiogenic EC behaviour on binding VEGFA or VEGFC and/or on interaction with VEGFR2 or VEGFR3. Activation of ephrin receptor B4 (EPHB4) upon interaction with its membrane-associated ligand, ephrin B2, may promote EC–EC repulsion or attraction in various cellular contexts and is essential for angiogenesis. Reverse EPHB4–ephrin B2 signalling may also play key parts in vascular development. Importantly, association of ephrin B2 with VEGFR2 or VEGFR3 promotes membrane internalization of the VEGFR and enhances angiogenic signalling. PLGF, placental growth factor.

(text from figure legend)

Reference

<pubmed>21860391</pubmed>| PMC3319719 | Nat Rev Mol Cell Biol.

Copyright

Reprinted by permission from Macmillan Publishers Ltd: [Nat Rev Mol Cell Biol.] (Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Herbert SP, Stainier DY. Nat Rev Mol Cell Biol. 2011 Aug 23;12(9):551-64. doi: 10.1038/nrm3176. Review. PMID: 21860391), copyright (2011)

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