B55PP2A Limits endothelial cell apoptosis during vascular remodeling: a complementary approach to kill pathological vessels?

ABSTRACT Rationale: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors. Objective: Starting from our previous observations that the PP2A phosphatase regulates the HIF/PHD2- constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion and oxygen restoration. Methods and Results: We show that the regulatory PP2A-phosphatase subunit B55 is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55 will counter cell stress conditions and thrive for stabilization and maturation. When B55 is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55/PP2A complex restrains PHD2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55 deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting nonpathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55-deficient vessels. Conclusions: Our data underline a unique role of the B55/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent anti-angiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF(R)-targeted therapies. Keywords: Angiogenesis, B55/PP2A-phosphatase, development, tumor progression, apoptosis, transgenic model