How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. However, 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. Starting from our previous observations that PP2A (protein phosphatase 2) regulates the HIF (hypoxia-inducible factor)/PHD-2 (prolyl hydroxylase 2)-constituted oxygen machinery, we hypothesized that this axis could play an essential role during blood vessel formation, tissue perfusion, and oxygen restoration.
We show that the PP2A regulatory subunit B55α is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55α counter cell stress conditions and thrive for stabilization and maturation. When B55α is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55α/PP2A complex restrains PHD-2 activity, promoting EC survival in a HIF-dependent manner, and dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow.
In conclusion, the data gathered underlines the B55α/PP2A phosphatase complex’s unique role in vessel remodeling and suggest the use of PP2A-inhibitors as potent antiangiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF-R (vascular endothelial growth factor receptor)-targeted therapies.
Ref: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.316071
