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

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 3

Tail swelling in absence of Adamts2.

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Tail swelling in absence of Adamts2. (A) Representative images of tails ...
(A) Representative images of tails from 8-week-old WT, TS2–/–, TS14–/–, and TS2–/–TS14–/– mice. Base tail diameters were measured (double arrows). Scale bar: 2 mm. As compared with those in WT mice, diameters were increased in TS2–/– and TS2–/–TS14–/– mice, suggesting potential lymphedema. (B) Hematoxylin and eosin staining of paraffin-embedded sections of tails was performed to further characterize the tissue compartment responsible for the increased diameter. Scale bar: 1 mm. The percentage of surface covered by the dermis (delimited by black dotted lines) was determined (ImageJ software) and was found to be increased in TS2–/– and TS2–/–TS14–/– mice. (C) Higher-magnification images of boxed regions in B show that the dermis is less stained in TS2–/– and TS2–/–TS14–/– mice because it is swollen and less dense. Scale bar: 50 μm. (D) Tail skins were removed and weighed (wet weight) and then dried for 72 hours in an oven at 60°C before being reweighed (dry weight) to determine the ratios of wet-to-dry weight. An increase of water content was confirmed 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; ***P < 0.001.