Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact

Citations to this article

RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development
Di Chen, … , Philip E. Lapinski, Philip D. King
Di Chen, … , Philip E. Lapinski, Philip D. King
Published June 11, 2019
Citation Information: J Clin Invest. 2019;129(9):3545-3561. https://doi.org/10.1172/JCI124917.
View: Text | PDF
Research Article Angiogenesis Vascular biology

RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development

  • Text
  • PDF
Abstract

Combined germline and somatic second-hit inactivating mutations of the RASA1 gene, which encodes a negative regulator of the Ras signaling pathway, cause blood and lymphatic vascular lesions in the human autosomal-dominant vascular disorder capillary malformation–arteriovenous malformation (CM-AVM). How RASA1 mutations in endothelial cells (ECs) result in vascular lesions in CM-AVM is unknown. Here, using different murine models of RASA1 deficiency, we found that RASA1 was essential for the survival of ECs during developmental angiogenesis, in which primitive vascular plexuses are remodeled into hierarchical vascular networks. RASA1 was required for EC survival during developmental angiogenesis, because it was necessary for export of collagen IV from ECs and deposition in vascular basement membranes. In the absence of RASA1, dysregulated Ras/MAPK signal transduction in ECs resulted in impaired folding of collagen IV and its retention in the endoplasmic reticulum (ER), leading to EC death. Remarkably, the chemical chaperone 4-phenylbutyric acid and small-molecule inhibitors of MAPK and 2-oxoglutarate–dependent collagen IV–modifying enzymes rescued ER retention of collagen IV and EC apoptosis and resulted in normal developmental angiogenesis. These findings have important implications for a better understanding of the molecular pathogenesis of CM-AVM and possible means of treatment.

Authors

Di Chen, Joyce M. Teng, Paula E. North, Philip E. Lapinski, Philip D. King

×

Loading citation information...
Advertisement
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts