The Angiomature project was structured to pursue three interrelated research lines (RL). RL1 was aimed at performing bulk and single cell analyses of the transcriptional and epigenetic program(s) of vascular maturation and organotypic differentiation during adolescence and aging. RL2 focused on the analysis of the functional consequences of program(s) and candidate molecules in cellular systems as well as in differentiating EC of adolescent mice and differentiated EC of adult mice and their adaptation to challenge. The most ambitious and logistically most challenging RL3 studies focused on changes of maturation and differentiation program(s) and vascular responses during aging. All three RLs have yielded important and groundbreaking discoveries. In RL1, we could in preclinical mouse models deconvolute on the systems level EC transcriptional programs (i) during development and adolescence, (ii) in the pre-metastatic and metastatic niches of the lung, (iii) spatially resolved in the homeostatic and challenged liver, and (iv) in the lungs during systemic aging. These experimental approaches yielded comprehensive systems maps that were in the liver expanded by proteomics and phosphoproteomics analyses to enable comprehensive datamining for novel organotypically and challenge-specifically expressed EC molecules to feed the pipeline for functional validation and proof-of-concept exploitation, which were pursued in RL2. RL2 led to important discoveries of organotypic angiocrine EC functions, notably, we (i) were able to show that the spatial zonation of the murine placental vasculature is specified by epigenetic mechanisms, (ii) focused on the liver to identify and validate on the basis of complex spatiotemporal transcriptomic, proteomic and phosphoproteomic systems maps a functional crosstalk between Wnt signaling and Angiopoietin/Tie signaling, (iii) elucidated the molecular machinery in endothelial cells that translate biomechanical sensing mechanisms into spatial angiocrine signaling cues that control metabolic liver zonation and liver regeneration, (iv) deconvoluted the interactions of metastasizing tumor cells and endothelial cells on the systems single cell level to identify critical mechanisms through which endothelial cell control fate decisions of metastasizing tumor cells in the metastatic vascular niche, (v) identified a subpopulation of LPL-expressing intratumoral endothelial cells that govern T-cell-mediated regression of low immunogenic tumors by serving as non-canonically antigen presenting cells, (vi) identified epigenetic enhancer modifications that determine the transition of angiogenic to the quiescent endothelial state, and (vii) showed that the Apelin-Apelin receptor system acts as a critical regulator of vascular aging being downregulated during aging in mouse and man controlling the susceptibility towards metastatic colonization
