VEGFD regulates blood vascular development by modulating SOX18 activity

Abstract

Key Points• Haploinsufficiency of Sox18 reveals an important role for VEGFD in regulating blood vascular development in vivo in vertebrates.• VEGFD acts through mitogenactivated protein kinase kinaseextracellular signal-regulated kinase to modulate the activity and nuclear concentration of endothelial-specific transcription factor SOX18.Vascular endothelial growth factor-D (VEGFD) is a potent pro-lymphangiogenic molecule during tumor growth and is considered a key therapeutic target to modulate metastasis. Despite roles in pathological neo-lymphangiogenesis, the characterization of an endogenous role for VEGFD in vascular development has remained elusive. Here, we used zebrafish to assay for genetic interactions between the Vegf/Vegf-receptor pathway and SoxF transcription factors and identified a specific interaction between Vegfd and Sox18. Double knockdown zebrafish embryos for Sox18/Vegfd and Sox7/Vegfd exhibit defects in arteriovenous differentiation. Supporting this observation, we found that Sox18/Vegfd double but not single knockout mice displayed dramatic vascular development defects. We find that VEGFD-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase signaling modulates SOX18-mediated transcription, functioning at least in part by enhancing nuclear concentration and transcriptional activity in vascular endothelial cells. This work suggests that VEGFD-mediated pathologies include or involve an underlying dysregulation of SOXF-mediated transcriptional networks. (Blood. 2014;123(7):1102-1112)

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

“…During primary angiogenesis in zebrafish, vegfc and vegfd are expressed in the DA and the trunk, respectively (Duong et al, 2014;Hogan et al, 2009b). Despite this, normal angiogenesis was observed in vegfc, vegfd double mutants and is also seen in flt4-null mutants (Kok et al, 2015).…”

“…However, phenotypes have been observed in postnatal settings (Paquet-Fifield et al, 2013) and during pathological processes (Stacker et al, 2001). Furthermore, Vegfd genetically interacts with Sox18 during mouse blood vascular development (Duong et al, 2014), suggesting its potential during embryonic development. Our findings are made by high-resolution quantitative analysis of lymphangiogenesis, including determining total LEC numbers per vessel.…”

“…We have recently found that vegfd is expressed throughout the embryonic trunk during zebrafish development (Duong et al, 2014), suggesting a potential function that remains to be fully explored. Here, we report the generation of a zebrafish vegfd mutant.…”

MicroRNA-199a-5p inhibits VEGF-induced tumorigenesis through targeting oxidored-nitro domain-containing protein 1 in human HepG2 cells

“…VEGF is one of the most potent stimulants of progression in several tumor types, mainly because it modulates its target transcription factors through multiple signaling pathways (7,8). Indeed, expression of signaling molecules in the VEGF pathway is elevated in several cardiovascular disorders including acute myocardial infarction, coronary artery disease and atherosclerosis (9)(10)(11).…”

Pulmonary Vasculopathy Associated with FIGF Gene Mutation

“…7e9 Furthermore, VEGF-D has been shown to modulate vessel development through sex determining region Yebox (SOX) 18. 7 Pathogenic mutations in FIGF have not yet been reported.…”