Aquaporin-1 sustains lymphangiogenic responses in inflammatory microenvironments

Abstract

Intestinal lymphatic vessels are essential for dietary lipid absorption and immune cell trafficking. Specialized villus lymphatic capillaries, lacteals, undergo constant VEGF-C-dependent renewal to maintain their function in a hyperosmolar, inflammatory microenvironment exposed to dietary by-products. The mechanisms of lacteal adaptation remain incompletely understood. We integrated new and published single-cell RNA-sequencing data to profile murine small-intestinal lymphatic endothelial cells (LECs) and identified three distinct subsets. Lacteal LECs display a transcriptional signature resembling Ptx3 immune-interacting LECs characterized by high expression of Aqp1, encoding the aquaporin-1 water channel. LEC-specific deletion of Aqp1 reduced lacteal length, impaired lipid uptake, and limited weight gain on a high-fat diet, underscoring the importance of water homeostasis in lacteal maintenance. AQP1 also promoted VEGF-C-dependent LEC migration under osmotic stress and, uniquely, was upregulated during inflammatory remodelling in secondary lymphedema and lymphatic malformations, but not during embryonic lymphangiogenesis. These findings link lacteal regeneration to inflammatory lymphatic remodelling and highlight tissue osmolarity as a key biophysical factor in postnatal lymphangiogenesis.