Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • 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
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Adrenomedullin signaling is necessary for murine lymphatic vascular development
Kimberly L. Fritz-Six, … , Manyu Li, Kathleen M. Caron
Kimberly L. Fritz-Six, … , Manyu Li, Kathleen M. Caron
Published December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):40-50. https://doi.org/10.1172/JCI33302.
View: Text | PDF
Research Article Article has an altmetric score of 3

Adrenomedullin signaling is necessary for murine lymphatic vascular development

  • Text
  • PDF
Abstract

The lymphatic vascular system mediates fluid homeostasis, immune defense, and tumor metastasis. Only a handful of genes are known to affect the development of the lymphatic vasculature, and even fewer represent therapeutic targets for lymphatic diseases. Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through the calcitonin receptor–like receptor (calcrl) when the receptor is associated with a receptor activity–modifying protein (RAMP2). Here we report on the involvement of these genes in lymphangiogenesis. AM-, calcrl-, or RAMP2-null mice died mid-gestation after development of interstitial lymphedema. This conserved phenotype provided in vivo evidence that these components were required for AM signaling during embryogenesis. A conditional knockout line with loss of calcrl in endothelial cells confirmed an essential role for AM signaling in vascular development. Loss of AM signaling resulted in abnormal jugular lymphatic vessels due to reduction in lymphatic endothelial cell proliferation. Furthermore, AM caused enhanced activation of ERK signaling in human lymphatic versus blood endothelial cells, likely due to induction of CALCRL gene expression by the lymphatic transcriptional regulator Prox1. Collectively, our studies identify a class of genes involved in lymphangiogenesis that represent a pharmacologically tractable system for the treatment of lymphedema or inhibition of tumor metastasis.

Authors

Kimberly L. Fritz-Six, William P. Dunworth, Manyu Li, Kathleen M. Caron

×

Figure 4

Differentiated lymph sacs and dermal lymphatics are present in AM signaling–null embryos.

Options: View larger image (or click on image) Download as PowerPoint
Differentiated lymph sacs and dermal lymphatics are present in AM signal...
Immunofluorescent staining of transverse sections through the jugular region (A–C) and sagittal sections through the skin (D and E) of E13.5 embryos. (A) Endothelial cells of lymph sacs from wild-type mice at E13.5 expressed VEGFR3 (red) and Prox1 (green). (B) Similar staining was observed in the lymph sacs of RAMP2–/– littermates. Nuclei stained with Hoechst are indicated in blue (A and B). (C) Prox1 (green) was also correctly coexpressed with PECAM (red) in lymph sacs of AM–/– embryos. (D and E) Dermal lymphatics (arrows) were present in wild-type (D) and RAMP2–/– (E) littermates at E14.5 as shown by VEGFR3 (red) and PECAM (green) staining. Dermal blood endothelium (arrowheads) expresses PECAM but not VEGFR3. n > 6 embryos per genotype. A, carotid artery, A; S, skin. Original magnification, ×200. Scale bar: 100 μM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 2 Wikipedia pages
102 readers on Mendeley
See more details