VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption.
Bottom Line: We show here that VEGF-C is necessary for perinatal lymphangiogenesis, but required for adult lymphatic vessel maintenance only in the intestine.VEGF-C was expressed by a subset of smooth muscle cells adjacent to the lacteals in the villus and in the intestinal wall.Our findings indicate that the lymphangiogenic growth factors provide trophic and dynamic regulation of the intestinal lymphatic vasculature, which could be especially important in the dietary regulation of adiposity and cholesterol metabolism.
Affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki University of Helsinki, Helsinki, Finland.Show MeSH
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Mentions: We further studied whether the reduction in dietary lipid absorption observed in the VCiΔR26 mice has an impact on diet-induced obesity in mice fed high-fat diet (HFD). Initial experiments in the 129SV/C57Bl/6J mixed genetic background did not reveal major differences in body weight, but indicated that the VCiΔR26 mice have an improved glucose metabolism compared to WT mice (Appendix Fig S5B and C). Interestingly, in the mixed background, the Vegfc-deleted mice had reduced serum cholesterol levels, whereas fecal cholesterol and free fatty acid (FFA) levels were increased in the VCiΔR26 mice, indicating impaired dietary lipid absorption (Appendix Fig S5D). We further performed HFD feeding experiments in the pure C57Bl/6J background, an established model of diet-induced obesity. We deleted Vegfc in 8-week-old male mice and started HFD feeding 4 weeks later. The VCiΔR26 mice gained significantly less weight and had better glucose tolerance than their WT littermates, independently of concurrent Vegfd deletion (Fig3A–C and Appendix Fig S5E and F). At necropsy after HFD, very low amounts of chyle were detected in one out of 16 Vegfc-deleted mice and in two out of five Vegfc- plus Vegfd-deleted mice, indicating mild lymphatic leakage. Body composition analysis showed that the VCiΔR26 mice had a significant reduction in total fat weight and fat percentage, but no changes in lean weight in comparison with WT littermates (Fig3D and Appendix Fig S5G). The changes in fat accumulation could not be explained by reduced caloric intake, since food consumption was similar between the VCiΔR26 and WT mice (Fig3E). As expected on the basis of our results from the mixed background, Vegfc deletion induced intestinal lymphatic vessel atrophy and increased lipid excretion into the feces also in the C57Bl/6J background (Fig3F–H). No difference in body weight was observed between WT and Vegfc-deleted mice on regular diet in which the majority of calories are derived from carbohydrate. This further indicates that the reduced body weight of the Vegfc-deleted mice on HFD is a result of reduced dietary lipid absorption.
Affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki University of Helsinki, Helsinki, Finland.