ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis

Janssen, Lauriane; Dupont, Laura; Bekhouche, Mourad; Noël, Agnès; Leduc, Cédric; Voz, Marianne; Peers, Bernard; Cataldo, Didier; Apte, Suneel S.; Dubail, Johanne; Colige, Alain

doi:10.1007/s10456-015-9488-z

Cited by 87 publications

(93 citation statements)

References 34 publications

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“…Thus, haploinsufficiency of ADAMTS3 is not pathogenic; 50% of enzyme is sufficient to cleave and activate enough VEGFC. This is in agreement with our previous observations that heterozygous Adamts3 þ/À mice were healthy and reproduced well (25).…”

Section: Discussionsupporting

confidence: 83%

“…In addition to endothelial cells, ADAMTS3 is significantly expressed in other tissues, such as in cartilage where it is considered to be the enzyme responsible for cleavage of the aminopropeptide of type II procollagen. Since our patients do not have developmental delay or major skeletal defects, it probably indicates that lack of ADAMTS3 secretion is compensated, at least partially, by another collagen aminopeptidase, likely ADAMTS2 (25). However, involvement of ADAMTS3 in type II procollagen maturation could explain the characteristic facial features of the subjects.…”

Section: Discussionmentioning

confidence: 84%

“…In contrast, the Adamts3 À/À mice died around E15.0 with severe edema due to complete lack of lymphatic vessels (25). Several hypotheses can be made to explain these differential effects.…”

Section: Discussionmentioning

confidence: 99%

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Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Brouillard

Dupont

Helaers

et al. 2017

Human Molecular Genetics

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103

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Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 84%

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Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Brouillard

Dupont

Helaers

et al. 2017

Human Molecular Genetics

Self Cite

103

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“…Recently, Adamts3 knockout embryos were show to be massively edematous and embryonically lethal after E15 and to lack any peripheral lymphatic vasculature. 87 Surprisingly, there was no evidence of a connective tissue phenotype although procollagen has been shown to be a major substrate for ADAMTS3. 87 Additional studies should elucidate the detailed cellular mechanisms of ADAMTS3 function, especially its effect on the directionality of LEC sprouting.…”

Section: Circulation Research February 5 2016mentioning

confidence: 99%

Lymphatic System in Cardiovascular Medicine

Aspelund

Robciuc

Karaman³

et al. 2016

Circulation Research

273

258

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Abstract:The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.

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“…So far, there are no data on the in vivo function of VEGF-C in hematopoiesis. However, recent reports indicate that Ccbe1 and Adamts3 are necessary for fetal erythropoiesis, 21,22 suggesting that VEGF-C has a potential function in hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%