Journal Article

VEGF‐C is required for intestinal lymphatic vessel maintenance and lipid absorption

Alitalo, Kari, Saharinen, Pipsa, Zheng, Wei, Zarkada, Georgia, Robciuc, Marius R, Nurmi, Harri

2015

Overview

Vascular endothelial growth factor C (VEGF‐C) binding to its tyrosine kinase receptor VEGFR‐3 drives lymphatic vessel growth during development and in pathological processes. Although the VEGF‐C/VEGFR‐3 pathway provides a target for treatment of cancer and lymphedema, the physiological functions of VEGF‐C in adult vasculature are unknown. We show here that VEGF‐C is necessary for perinatal lymphangiogenesis, but required for adult lymphatic vessel maintenance only in the intestine. Following Vegfc gene deletion in adult mice, the intestinal lymphatic vessels, including the lacteal vessels, underwent gradual atrophy, which was aggravated when also Vegfd was deleted. VEGF‐C was expressed by a subset of smooth muscle cells adjacent to the lacteals in the villus and in the intestinal wall. The  Vegfc‐ deleted mice showed defective lipid absorption and increased fecal excretion of dietary cholesterol and fatty acids. When fed a high‐fat diet, the Vegfc ‐deficient mice were resistant to obesity and had improved glucose metabolism. 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. Synopsis A new mouse model allows effective, timed and long lasting deletion of vascular endothelial growth factor C (VEGF‐C) by the Cre‐Lox system and highlights its relevance for intestinal lymphatic vessel maintenance and lipid absorption. Vegfc deletion halted the growth of lymphatic vessels at all stages of development. In adults with a normally developed lymphatic system, Vegfc deficiency specifically induced intestinal lymphatic vessel atrophy. Lymphatic vessel atrophy in the adult intestine had no impact on animal welfare but reduced dietary lipid uptake and high fat diet‐induced obesity. Graphical Abstract A new mouse model allows effective, timed and long lasting deletion of vascular endothelial growth factor C (VEGF‐C) by the Cre‐Lox system and highlights its relevance for intestinal lymphatic vessel maintenance and lipid absorption.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley & Sons, Ltd,Springer Nature
• Subject: Adipose tissue / Animals / Atrophy / Cancer / Cholesterol / Clinical trials / Clonal deletion / EMBO11 / EMBO46 / Excretion / Experiments / Fatty acids / Gene Deletion / Glucose metabolism / Growth factors / High fat diet / Intestine / Intestines - physiology / Laboratory animals / lipid absorption / Lipid Metabolism / Lipids / Lymphatic system / lymphatic vasculature / Lymphatic Vessels - physiology / Lymphedema / Medical research / Mice / Mice, Knockout / Nutrient deficiency / obesity / Oils & fats / Protein-tyrosine kinase receptors / Rodents / Smooth muscle / Vascular endothelial growth factor / Vascular endothelial growth factor C / Vascular Endothelial Growth Factor C - genetics / Vascular Endothelial Growth Factor C - metabolism / Vascular endothelial growth factor receptors / VEGF‐C / Villus