Wnt/frizzled Signaling in Endothelium: A Major Player in Blood-Retinal- and Blood-Brain-Barrier Integrity

The Wnt/frizzled signaling pathway is one of the major regulators of endothelial biology, controlling key cellular activities.Many secreted Wnt ligands have been identified and can initiate diverse signaling via binding to a complex set of Frizzled (Fzd) transmembrane receptors and coreceptors.Roughly, Wnt signaling is subdivided into two pathways: the canonical Wnt/βcatenin signaling pathway whose main downstream effector is the transcriptional coactivator βcatenin, and the noncanonical Wnt signaling pathway, which is subdivided into the Wnt/Ca 2+ pathway and the planar cell polarity pathway.Here, we will focus on its cross talk with other angiogenic pathways and on its role in blood-retinal-and blood-brain-barrier formation and its maintenance in a differentiated state.We will unravel how retinal vascular pathologies and neurovascular degenerative diseases result from disruption of the Wnt pathway related to vascular instability, and highlight current research into therapeutic options.T he Wnt signaling pathway is one of the main regulators of endothelial biology.In mammals, 19 different Wnt secreted ligands have been identified to date (Nusse and Clevers 2017); they can initiate distinct signaling upon binding at the cell surface to a combination of multiple transmembrane receptors of the Frizzled (Fzd) family (10 in humans and mice), and low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) coreceptors (Gordon and Nusse 2006).Wnt proteins are highly hydro-phobic and posttranslationally modified with lipids by the membrane-bound-O-acyltransferase porcupine (PORCN), restricting their diffusion in the aqueous environment primarily toward neighboring cells (Willert et al. 2003;Takada et al. 2006).Studies of their crystal structures show that its lipid tail is required for Wnt interaction within the Fzd extracellular cysteinerich domain (Janda et al. 2012).Wnt secretion relies on the conserved multipass transmembrane and putative sorting receptor Wntless 4 These authors contributed equally to this work.