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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.
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Research Article Angiogenesis Vascular biology

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

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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

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Figure 4

Absence of Adamts2 and/or Adamts14 affects the lymphatic network under physiological conditions in adult mice.

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Absence of Adamts2 and/or Adamts14 affects the lymphatic network under p...
(A) Whole mounts of dorsal ear skin were stained with an antibody specific for LYVE1 for immunofluorescence visualization of lymphatics. Scale bar: 1 mm. (B) For computerized quantification, lymphatic vessel frequencies were determined according to the distance from the border of the ear, because the structure and density of the lymphatic network vary according to the distance from the ear edge. The shapes of the distribution curves were found to be statistically different (Kolmogorov-Smirnov test; significance levels were adjusted with Bonferroni’s correction for multicomparison). The most dramatic reduction was observed in TS2–/–TS14–/– mice, but it was also found to be reduced in TS2–/– and TS14–/– mice as compared with WT mice. By sharp contrast, no difference was seen regarding blood vessels, showing that these alterations affect lymphatics specifically (Supplemental Figure 5). (C) Computerized quantifications of mean diameter of the lymphatic vessels were also performed and demonstrated a smaller diameter in TS2–/– and TS2–/–TS14–/– mice. Statistical analyses were performed using Kruskal-Wallis test followed by Holm-Šidák post hoc test for multiple comparisons. *P < 0.05; **P < 0.01.

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

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