Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in adults for pro-VEGFC activation and lymphatic homeostasis
Laura Dupont, … , Agnès Noël, Alain C.M.A. Colige
Laura Dupont, … , Agnès Noël, Alain C.M.A. Colige
Published March 22, 2022
Citation Information: JCI Insight. 2022;7(8):e151509. https://doi.org/10.1172/jci.insight.151509.
View: Text | PDF
Research Article Angiogenesis Vascular biology

ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in adults for pro-VEGFC activation and lymphatic homeostasis

  • Text
  • PDF
Abstract

The capacity of ADAMTS3 to cleave pro-VEGFC into active VEGFC able to bind its receptors and to stimulate lymphangiogenesis has been clearly established during embryonic life. However, this function of ADAMTS3 is unlikely to persist in adulthood because of its restricted expression pattern after birth. Because ADAMTS2 and ADAMTS14 are closely related to ADAMTS3 and are mainly expressed in connective tissues where the lymphatic network extends, we hypothesized that they could substitute for ADAMTS3 during adulthood in mammals allowing proteolytic activation of pro-VEGFC. Here, we demonstrated that ADAMTS2 and ADAMTS14 are able to process pro-VEGFC into active VEGFC as efficiently as ADAMTS3. In vivo, adult mice lacking Adamts2 developed skin lymphedema due to a reduction of the density and diameter of lymphatic vessels, leading to a decrease of lymphatic functionality, while genetic ablation of Adamts14 had no impact. In a model of thermal cauterization of cornea, lymphangiogenesis was significantly reduced in Adamts2- and Adamts14-KO mice and further repressed in Adamts2/Adamts14 double-KO mice. In summary, we have demonstrated that ADAMTS2 and ADAMTS14 are as efficient as ADAMTS3 in activation of pro-VEGFC and are involved in the homeostasis of the lymphatic vasculature in adulthood, both in physiological and pathological processes.

Authors

Laura Dupont, Loïc Joannes, Florent Morfoisse, Silvia Blacher, Christine Monseur, Christophe F. Deroanne, Agnès Noël, Alain C.M.A. Colige

×

Figure 2

Phosphorylation of VEGFR3 by pro-VEGFC activated or not by ADAMTS3, ADAMTS2, or ADAMTS14.

Options: View larger image (or click on image) Download as PowerPoint
Phosphorylation of VEGFR3 by pro-VEGFC activated or not by ADAMTS3, ADAM...
Conditioned medium from HEK293 cells expressing full-length pro-VEGFC was first incubated for 18 hours with buffer alone (lane 1, negative control), ADAMTS3 (as positive control), ADAMTS2, or ADAMTS14, in the presence or absence of EDTA used as inhibitor. These different pretreated media were then added (20 μL or 100 μL) into 1 mL of serum-free EBM-2 on LEC cultures. (A) After 5 minutes, cells were lysed, and phosphorylated VEGFR3 (pVEGFR3) was visualized by Western blotting. (B) After stripping of the antibodies, the same membrane was then used to visualize total VEGFR3. Treatment of the pro-VEGFC–rich conditioned medium with active ADAMTS3, ADAMTS2, and ADAMTS14 induced the phosphorylation of the 3 bands corresponding to VEGFR3 (arrows) in a dose-dependent manner, while the total amount of VEGFR3 was not affected, demonstrating that processing of pro-VEGFC by ADAMTS2, ADAMTS3, or ADAMTS14 leads to the activation of pro-VEGFC in a similar manner.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts