Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in approximately half of sporadic (non-familial) VMs, with the cause of the remaining cases unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully

Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1-mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch–PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis.

Highlights d OPA1 is upregulated in response to angiogenic stimuli to limit NFkB signaling d OPA1 controls cytosolic Ca 2+ levels, NFkB signaling, and angiogenic gene expression d Deletion of endothelial Opa1 curtails tumor angiogenesis, growth, and metastatization d MYLS22, first-in-class small molecule, inhibits OPA1 and limits tumor growth