Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells

Arterial blood transport into peripheral organs is indispensable for developmental growth, homeostasis and tissue repair. While it is appreciated that defective formation or compromised function of arteries is associated with a range of human diseases, the cellular and molecular mechanisms mediating arterial development remain little understood for most organs. Here, we show with genetic approaches that a small subpopulation of endothelial cells inside the intestinal villi of the embryonic mouse, characterized by the expression of endothelial cell-specific molecule 1 (Esm1/endocan), gives rise to arterial endothelium in the intestinal wall but also in the distant mesenteric vasculature. This involves cell migration but also substantial changes in morphology and gene expression. Immunohistochemistry and single cell RNA-sequencing confirm that intestinal Esm1⁺ cells have a distinct molecular profile and the capacity to undergo arterial differentiation. Genetic approaches establish that artery formation by the progeny of Esm1⁺ cells requires integrin β1 and signaling by the growth factor VEGF-C and its receptor VEGFR3. The sum of these findings demonstrates that Esm1⁺ cells inside the villus capillary network contribute to the formation of intestinal and mesenteric arteries during development.