A research team from the Guangzhou Institutes of Biomedicine and Health of the Chinese Academy of Sciences, in collaboration with South China University of Technology, Guangzhou National Laboratory and Westlake University, has constructed a mouse endothelial development atlas spanning the full embryonic stages and revealed that endothelial cells begin organ-specific differentiation as early as mid-gestation.

Their findings were recently published in the journal Cell.

The study identifies Casz1 as a lung-enriched endothelial gene that supports pulmonary vascular growth, organ-specific endothelial maturation, and communication between endothelial and epithelial cells in the lung.

Blood vessels extend throughout the vertebrate body. Beyond transporting blood, they help regulate tissue repair and regeneration. Endothelial cells line the interior of blood vessels and form their core structural layer. While arterial and venous endothelial differentiation has been well characterized, how endothelial cells acquire organ-specific identities — and why this is physiologically important — remains poorly understood.

To address this knowledge gap, the researchers established an endothelial developmental atlas covering the entire mouse embryonic period, with data from eight organs and 26 time points. Endothelial cells were detectable as early as embryonic day 7 (E7). Organ-specific differentiation of endothelial cells began at E8 in cardiac endothelial cells (endocardium) and expanded across multiple organs during mid-gestation (E9.0–E13.5), including the central nervous system, liver, lung and digestive tract. After mid-gestation, inter-organ endothelial differences became increasingly distinct, marked by enhanced activation of organ-specific gene programs and signaling pathways consistent with each organ's physiological functions.

This atlas enabled the identification of previously unrecognized lung endothelium-enriched genes, including Casz1.

Endothelial-specific deletion of Casz1 disrupted lung vascular development and prevented lung endothelial cells from adopting organ-specific properties. Mechanistically, Casz1 binds to promoter regions in lung endothelial chromatin and regulates the expression of key genes involved in pulmonary vascular development and maturation, such as Vegfr2, Foxf1 and Car4.

Loss of Casz1 in endothelial cells also decreased the number of NKX2.1⁺ and SFTPC+ alveolar epithelial cells, delayed their proliferation, and weakened endothelial–epithelial crosstalk. The team found these effects were linked to reduced endothelial secretion of FGF1, suggesting that Casz1 contributes to alveolar development in part by modulating endothelial paracrine signaling.

This study presents a comprehensive endothelial developmental atlas across 26 embryonic time points and defines the timing and molecular characteristics of organ-specific endothelial cells. Using the lung as a model, the research further links organ-specific endothelial maturation to local tissue development via endothelial–epithelial signaling. The researchers noted that these findings establish a foundation for investigating how organ-specific vascular properties shape development and disease.