Writ/Frizzled Signaling in the Vasculature: New Angiogenic Factors in Sight

摘要

Wnt growth factors function via Frizzled receptors to affect cellular proliferation, differentiation, apoptosis, and migration. Wnt/Frizzled signaling is now linked to human hereditary disorders with retinal vascular defects, implicating Wnts as angiogenic factors. Here, we discuss Wnts and a novel Frizzled ligand, Norrin, in physiological and pathological angiogenesis. Wnts are secreted, cysteine-rich glycoproteins that bind and activate Frizzled receptors, a family of seven trans-membrane domain proteins. Current knowledge of Wnt signaling has been garnered from a variety of organisms, including mouse, fly, zebrafish, Xenopus laevis, and using mammalian cultured cells (73). Wnts govern cell proliferation, survival, differentiation, polarization, and migration by modulating both cellular and transcriptional events (49). Based on studies in mice, Wnts function during mammalian development, but Wnt signaling is also commonly altered in human cancers. The signaling cascades defined for Wnt/Frizzledsare uniquely distinct from other receptor-mediated pathways, but their diversity of cellular outputs still presents a challenge to our understanding of how Wnts work. Cellular activities governed by Wnts are also those that are critical for vascular development and angiogenesis, the process by which new blood vessels sprout from preexisting ones. Thus one might expect that Wnts would be implicated as angiogenic factors. The focus of this review is on recent studies exploring the hypothesis that Wnts areangiogenic factors and on the discovery of human retinal vascular disorders associated with Frizzleds. We will briefly overview the mechanisms of intracellular Wnt signaling, evaluate genetic and biochemical evidence that Wnts act in vascular development, and describe a novel Frizzled ligand, Norrin. These studies place Wnt/Frizzled signaling central to the development of retinal vasculature. The evidence that Wnt/Frizzled represents a novel angiogenic signaling pathway is now in sight.