Aquaporin-1 sustains lymphangiogenic responses in hyperosmotic inflammatory microenvironments

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Abstract
Intestinal lymphatic vessels are essential for dietary lipid absorption and immune cell trafficking. Villus lymphatic capillaries, lacteals, undergo continuous VEGF-C–dependent renewal to function in a hyperosmolar, inflammatory environment exposed to dietary and microbial by-products. To define mechanisms underlying this adaptation, we integrated new and published single-cell RNA-sequencing datasets of murine small intestinal lymphatic endothelial cells (LECs). Lacteal LECs resembled Ptx3+ immune-interacting LECs and were characterized by high expression of water channel AQP1. LEC-specific Aqp1 deletion reduced lacteal length, impaired lipid uptake, and limited weight gain on a high-fat diet, while mosaic deletion revealed a cell-autonomous requirement for AQP1 in LEC positioning at hyperosmolar tip regions. AQP1 promoted LEC migration under hyperosmotic stress by preserving cytoskeletal and junctional remodeling and alleviating osmotic stress–induced transcriptional programs. AQP1 was upregulated during inflammatory remodeling in lymphedema and lymphatic malformations, but not during embryonic lymphangiogenesis. These findings link lacteal regeneration to inflammatory lymphatic remodeling and highlight tissue osmolarity as a biophysical determinant of postnatal lymphangiogenesis.
Funding Information
  • European Union’s Horizon 2020 (847939)
  • European Union’s Horizon 2020 (814316)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSK-3_190435)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (30105_156266)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (30105_212387)
  • Human Frontier Science Program (LT000074/2019-L)
  • Human Frontier Science Program (LT000633/2020-L)
  • Muschamps Foundation
  • Fonds De La Recherche Scientifique - FNRS

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