A model for the role of ALK-1 and endoglin in normal angiogenesis

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A model for the role of ALK-1 and endoglin in normal angiogenesis A model for the role of ALK-1 and endoglin in normal angiogenesis. TGF-β can signal via two distinct receptor-mediated pathways in endothelial cells. TβR-I is a high-affinity receptor that activates a pathway that includes Smad2/3 and Smad4 complexes, which may lead to transcription activation of genes involved in the activation phase of angiogenesis. ALK-1 is a lower-affinity receptor for TGF-β that signals through a pathway that includes Smad1/5 and Smad4, which may lead to transcriptional activation of genes that are involved in the resolution phase of angiogenesis. Endoglin is a negative modulator of TGF-β signaling through the TβR-I receptor, although its role in signaling via the ALK-1 receptor is less clear. Low concentrations of TGF-β ligand would favor the high-affinity TβR-I receptor, shifting the balance of signal transduction toward the activation phase of angiogenesis. High concentrations would be required to activate the ALK-1 pathway and to induce a shift to the resolution phase. Mutations in the ALK-1 gene would reduce signaling through this receptor, thus favoring signaling through the TβR-I receptor and the activation phase of angiogenesis. Mutations in endoglin would have a similar effect, removing the negative modulation of TGF-β through the TβR-I receptor, thereby shifting the balance of signal to favor the activation phase. This model assumes that endoglin enhances (or at least does not inhibit) ALK-1 receptor-mediated signaling. Source: Hereditary Hemorrhagic Telangiectasia, The Online Metabolic and Molecular Bases of Inherited Disease Citation: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. The Online Metabolic and Molecular Bases of Inherited Disease; 2014 Available at: https://ommbid.mhmedical.com/DownloadImage.aspx?image=/data/books/971/ch212fg2.png&sec=62658467&BookID=971&ChapterSecID=62658397&imagename=&gboscontainerID=0 Accessed: December 29, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved