Incongruence between transcriptional and vascular pathophysiological cell states

The Notch pathway is a major regulator of transcriptional specification and vascular biology. Previous studies have suggested that targeting the ligand Dll4 or the Notch-receptors results in similar molecular and angiogenesis outcomes. Here, we analyzed single and compound genetic mutants for all Notch signaling members and found very significant differences in the way ligands and receptors regulate vascular homeostasis. Loss of Notch receptors, leads to minor vascular pathology featuring hypermitogenic MAPK-driven cell-cycle arrest and senescence. In contrast, loss of Dll4 triggers a strong Myc-driven switch towards cell proliferation and sprouting and major organ pathology. Targeting of Myc completely suppressed the proliferative and tip-cell angiogenic states induced by Dll4 loss-of-function, however, this did not avoid vascular pathology. Only VEGF blockade prevented the pathology induced by Dll4 loss, but without fully suppressing its transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states and adult vascular phenotypes and related pathophysiology.