Incongruence between transcriptional and vascular pathophysiological cell states

Abstract The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all signaling members, we find significant differences in way ligands regulate liver vascular homeostasis. Loss caused hypermitogenic cell-cycle arrest senescence. Conversely, Dll4 loss triggered strong Myc-driven switch inducing proliferation tip-cell state. Myc suppressed induction angiogenesis absence Dll4, without preventing enlargement organ pathology. Similarly, inhibition other pro-angiogenic pathways, including MAPK/ERK mTOR, had no effect on expansion induced loss; however, anti-VEGFA treatment prevented it fully suppressing metabolic programs. This study shows incongruence between single-cell states, phenotypes related pathophysiology. Our findings also suggest that structure abnormalization, rather than neoplasms, causes reported anti-Dll4 antibody toxicity.