ADAMTS2 and ADAMTS14 substitute ADAMTS3 in adults for proVEGFC activation and lymphatic homeostasis.

The capacity of ADAMTS3 to cleave proVEGFC into active VEGFC able to bind its receptors and to stimulate lymphangiogenesis has been clearly established during the embryonic life. However such function of ADAMTS3 is unlikely to persist in adulthood because of its restricted expression pattern after birth. Since 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 ADAMTS3 during adulthood in mammals for proteolytic activation of proVEGFC. Here, we demonstrated that ADAMTS2 and ADAMTS14 are able to process proVEGFC and activate the downstream pathway as efficiently as ADAMTS3. In vivo, adult mice lacking Adamts2 develop 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 has no impact. In a model of thermal cauterization of cornea, lymphangiogenesis was significantly reduced in Adamts2 and Adamts14 knockout mice, and further repressed in Adamts2/Adamts14 double knockout mice. In summary, we have demonstrated that ADAMTS2 and ADAMTS14 are as efficient as ADAMTS3 for proVEGFC activation and are involved in the homeostasis of the lymphatic vasculature in adulthood, both in physiological and pathological processes.