Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • 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 ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • 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
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice
Philip E. Lapinski, … , Eva Sevick-Muraca, Philip D. King
Philip E. Lapinski, … , Eva Sevick-Muraca, Philip D. King
Published January 9, 2012
Citation Information: J Clin Invest. 2012;122(2):733-747. https://doi.org/10.1172/JCI46116.
View: Text | PDF
Research Article Angiogenesis

RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice

  • Text
  • PDF
Abstract

RASA1 (also known as p120 RasGAP) is a Ras GTPase–activating protein that functions as a regulator of blood vessel growth in adult mice and humans. In humans, RASA1 mutations cause capillary malformation–arteriovenous malformation (CM-AVM); whether it also functions as a regulator of the lymphatic vasculature is unknown. We investigated this issue using mice in which Rasa1 could be inducibly deleted by administration of tamoxifen. Systemic loss of RASA1 resulted in a lymphatic vessel disorder characterized by extensive lymphatic vessel hyperplasia and leakage and early lethality caused by chylothorax (lymphatic fluid accumulation in the pleural cavity). Lymphatic vessel hyperplasia was a consequence of increased proliferation of lymphatic endothelial cells (LECs) and was also observed in mice in which induced deletion of Rasa1 was restricted to LECs. RASA1-deficient LECs showed evidence of constitutive activation of Ras in situ. Furthermore, in isolated RASA1-deficient LECs, activation of the Ras signaling pathway was prolonged and cellular proliferation was enhanced after ligand binding to different growth factor receptors, including VEGFR-3. Blockade of VEGFR-3 was sufficient to inhibit the development of lymphatic vessel hyperplasia after loss of RASA1 in vivo. These findings reveal a role for RASA1 as a physiological negative regulator of LEC growth that maintains the lymphatic vasculature in a quiescent functional state through its ability to inhibit Ras signal transduction initiated through LEC-expressed growth factor receptors such as VEGFR-3.

Authors

Philip E. Lapinski, Sunkuk Kwon, Beth A. Lubeck, John E. Wilkinson, R. Sathish Srinivasan, Eva Sevick-Muraca, Philip D. King

×

Figure 1

Absence of blood vessel abnormalities in induced RASA1-deficient mice.

Options: View larger image (or click on image) Download as PowerPoint
Absence of blood vessel abnormalities in induced RASA1-deficient mice.
(...
(A) Whole mount staining of ear and diaphragm from Rasa1fl/flUbert2cre transgenic and Rasa1fl/fl control mice (treated with TM 4 months prior) for the BEC marker CD31. (B) Adult Rosa26eyfp and Rosa26eyfpUbert2cre mice were administered TM at 2 months of age and again 10 days later. 7 days after the last TM injection, whole mount ear and thoracic diaphragm specimens were stained with anti-GFP antibodies to identify sites of YFP expression (green) and anti-CD31 antibodies to identify blood vessels (red). Merged red and green fluorescence images are shown for ear; individual and merged images are shown for diaphragm. The same results were obtained in 6 repeat experiments (n = 6 mice). Original magnification, ×40 (A); ×100 (B).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts