Nature Communications | Study on a Novel Mechanism of Intestinal and Mesenteric Artery Formation

This study first reveals the critical role of Esm1+ endothelial cells in intestinal and mesenteric artery generation during embryonic development, and identifies the necessity of Itgb1 and VEGF-C/VEGFR3 signaling pathways. It provides new mechanistic insights and therapeutic strategies for arterial development-related diseases.

 

Literature Overview
The article titled 'Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells' published in Nature Communications reviews mechanisms of intestinal artery formation during embryonic development, focusing on the origin, migration capability, and molecular features of Esm1+ endothelial cells. Using genetic lineage tracing, immunohistochemistry, and single-cell RNA sequencing, this work characterizes the functional dynamics of these cells and analyzes the role of Itgb1 and VEGF-C/VEGFR3 signaling in arterial network formation. The content is logically structured with professional terminologies.

Background Knowledge
Artery formation is a critical process in organ development, homeostasis maintenance, and tissue repair. While previous studies have elucidated mechanisms of early dorsal aorta and cardinal vein formation, molecular regulation of intestinal and mesenteric artery development during embryogenesis and postnatal stages remains poorly understood. Esm1 (endothelial cell-specific molecule 1), a well-established tip cell marker, plays essential roles in retinal and cardiac artery formation. This study first demonstrates that Esm1+ cells not only reside in intestinal villus capillary networks but also migrate into intestinal wall and mesenteric arteries, undergoing significant morphological and gene expression transitions. The research further identifies key roles for Itgb1 and VEGF-C/VEGFR3 signaling pathways in Esm1+ cell transformation to arterial endothelium, filling critical knowledge gaps in intestinal artery development. These findings establish cellular and molecular foundations for studying diseases involving arterial developmental disorders.

 

 

Research Methods and Experiments
This study employed Esm1-CreERT2 transgenic mice with a Rosa26-mTmG reporter system for genetic lineage tracing, combined with immunohistochemistry and single-cell RNA sequencing (scRNA-seq) to analyze molecular characteristics of Esm1+ cells and their contributions to intestinal and mesenteric artery formation. Additionally, Itgb1 knockout and Vegfc-inactivated mouse models were used to assess dependencies of Esm1+ cells on specific signaling pathways during artery formation. Comparative transcriptomic analysis between retinal and intestinal Esm1+ cells was performed to identify tissue-specific functional differentiation.

Key Conclusions and Perspectives

• Esm1+ endothelial cells establish a unique molecular signature in embryonic intestinal villi with the capacity to differentiate into arterial endothelium.
• These cells contribute to both intestinal wall arteries and mesenteric arteries through migratory expansion.
• Itgb1 is essential for Esm1+ cell-mediated arterial genesis, with gene deletion causing reduced mesenteric artery diameter and cellular morphological abnormalities.
• VEGF-C/VEGFR3 signaling is required for Esm1+ cell migration and expansion of the arterial network, with pathway disruption leading to defective artery formation.
• scRNA-seq analysis demonstrates that Esm1+ cells undergo cell cycle arrest and gene expression reprogramming during transition to Bmx+ arterial endothelial cells.
• Postnatally, Esm1+ cells persist in intestinal capillaries but lose capacity to contribute to mesenteric large artery formation.
• This work reveals distinct molecular signatures and microenvironment dependencies between intestinal and retinal artery development.

Research Significance and Prospects
The study provides novel mechanistic insights into organ-specific artery formation and defines Esm1+ cells as intestinal artery progenitors. Future investigations should explore functional dynamics of these cells in disease models and evaluate therapeutic potential of targeting VEGF-C/VEGFR3 and Itgb1 signaling pathways, offering innovative strategies for congenital arterial anomalies and related vascular diseases.

 

 

Conclusion
This systematic investigation clarifies the role of Esm1+ endothelial cells in embryonic intestinal and mesenteric artery development, demonstrating their dependence on Itgb1 and VEGF-C/VEGFR3 signaling pathways. Through multi-omics analysis and genetic tools, the research team characterized molecular features and functional transitions of Esm1+ cells during arterial maturation. These findings expand current understanding of endothelial heterogeneity and provide theoretical foundations for mechanistic studies and targeted therapies of arteriovenous malformations and intestinal ischemic diseases. Future research directions include functional analysis of this signaling axis in disease models and exploring applications in tissue engineering and regenerative medicine.

 

Esther Bovay, Kai Kruse, Emma C Watson, Mark L Kahn, and Ralf H Adams. Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells. Nature Communications.