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B55α/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complementary Approach To Kill Pathological Vessels?

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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 non-pathological 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.

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(c) American Heart Association et al, 2020

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Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

# metadata.dc.title[].value
B55α/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complementary Approach To Kill Pathological Vessels?