Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD

Bui, Hung; Enis, David R.; Robciuc, Marius R.; Nurmi, Harri; Cohen, Jozef; Chen, Mei; Yang, Yi‐Qing; Dhillon, Veerpal; Johnson, Kathy; Zhang, Hong; Kirkpatrick, Robert B.; Traxler, Elizabeth A.; Anisimov, Andrey; Alitalo, Kari; Kahn, Mark L.

doi:10.1172/jci83967

Cited by 112 publications

(133 citation statements)

References 47 publications

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“…This resembles the processing of mammalian/human VEGFD, via the proprotein convertases furin, PC5 and PC7 (McColl et al, 2003(McColl et al, , 2007, and the processing of zebrafish Vegfc, which likely requires the proprotein convertases furin, PC5 and PC7 (Khatib et al, 2010), similar to requirements in mammalian systems (Joukov et al, 1996;Siegfried et al, 2003). Activation of VEGFC requires CCBE1 and ADAMSTS3, but VEGFD is not processed in a CCBE1-dependent manner in these mammalian models (Bui et al, 2016;Jeltsch et al, 2014). By contrast, in zebrafish-overexpression models it was shown that Vegfd activity is Ccbe1 dependent .…”

Section: Discussion a Role For Vegfd In Developmental Angiogenesis Anmentioning

confidence: 72%

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

et al. 2017

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Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, giving rise to veins and lymphatics. Vegfd has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context-specific indispensable and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis.

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Section: Discussion a Role For Vegfd In Developmental Angiogenesis Anmentioning

confidence: 72%

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

et al. 2017

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“…Previous data have established that VEGF-C, like ELA/APJ, is specifically required for SV sprouting (Chen et al, 2014b). We investigated SOX17 expression in mice lacking a VEGF-C pathway member, CCBE1, which is required for its function (Bui et al, 2016; Hogan et al, 2009). Ccbe1 KO mice displayed the same coronary phenotype as Vegfc mutants (Figure S6), and SOX17 was increased in coronary-deficient regions (Figures 5E and 5F).…”

Section: Resultsmentioning

confidence: 99%

Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

Sharma

Ford

et al. 2017

Developmental Cell

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SUMMARY Organogenesis during embryonic development occurs through the differentiation of progenitor cells. This process is extraordinarily accurate, but the mechanisms ensuring high fidelity are poorly understood. Coronary vessels of the mouse heart derive from at least two progenitor pools, the sinus venosus and endocardium. We find that the ELABELA (ELA)-APJ signaling axis is only required for sinus venosus-derived progenitors. Because they do not depend on ELA-APJ, endocardial progenitors are able to expand and compensate for faulty sinus venosus development in Apj mutants, leading to normal adult heart function. An upregulation of endocardial SOX17 accompanied compensation in Apj mutants, which was also seen in Ccbe1 knockouts, indicating that the endocardium is activated in multiple cases where sinus venosus angiogenesis is stunted. Our data demonstrate that by diversifying their responsivity to growth cues, distinct coronary progenitor pools are able to compensate for each other during coronary development, thereby providing robustness to organ development.

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“…Indeed, lack of the C-terminal domain mimics the Ccbe1 knockout (22). The ADAMTS3-CCBE1 complex can also form independently of VEGFR3 and cleave VEGFC, but proper localization is required for adequate lymphangiogenesis (23). ADAMTS3 seems a requisite for this.…”

Section: Discussionmentioning

confidence: 99%

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Brouillard

Dupont

Helaers

et al. 2017

Human Molecular Genetics

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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Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD

Cited by 112 publications

References 47 publications

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

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