Deletion of Vascular Endothelial Growth Factor C (VEGF-C) and VEGF-D Is Not Equivalent to VEGF Receptor 3 Deletion in Mouse Embryos

Abstract

Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3 −/− embryos, the Vegfc −/−; Vegfd −/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3 −/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3 neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc +/− mice in the K14-VEGF-D; Vegfc +/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.

Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

“…The generation of K14-VEGF-A Tg mice that express mouse VEGF-A164 under control of the K14 promoter, of K14-VEGF-C Tg mice that express human VEGF-C, and of K14-VEGF-D Tg mice that express mouse VEGF-D has been described previously Detmar et al, 1998;Xia et al, 2003;Haiko et al, 2008). K14-VEGF-A, K14-VEGF-C, and K14-VEGF-D Tg mice (all FVB genetic background) were bred and housed in the animal facility of ETH Zurich.…”

“…K14-VEGF-A+C and K14-VEGF-A+D double Tg mice were generated by crossing homozygous VEGF-A and hemizygous VEGF-C or VEGF-D Tg mice, respectively. The mice were genotyped as previously described Haiko et al, 2008). Untreated FVB wild-type mice were used as controls.…”

Advances in the research on lymphangiogenesis in carcinoma tissues (Review)

“…Haiko et al investigated a mutant mouse model in which the mutation site was located downstream of the VEGFR-3 gene. The results revealed that dysgenopathy of lymphatic vessels in Vegfc +/-mice was ameliorated after Kemurinein 14 promoters induced the overexpression of the human or mouse VEGF-D gene in the mice (19). Therefore, the VEGF-C/VEGF-D/VEGFR-3 signaling pathways play an important role in the regulation of the tumor lymphangiogenesis process.…”

“…Currently, the VEGF-C/VEGF-D/ VEGFR-3 signaling pathways are believed to be the most important mechanism underlying tumor lymphangiogenesis (16)(17)(18)(19)(20)(21)(22).…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…As mice deWcient in both Vegfc and Vegfd, unlike Vegfr3 null mice, have normal blood vascular development (Haiko et al 2008), it is likely that other VEGFR-3 ligands, such as integrins, contribute to VEGFR-3 signaling in blood vascular endothelium. Additional VEGF-C signal transduction pathways were also described, such as interaction of VEGF-C with neuropilin-2 (NP2) and integrin 9.…”