Pak1 plays an important role in several cellular processes, including cell migration, but its role in
pathological angiogenesis is not known. Here, we have determined its role in pathological
retinal angiogenesis using an
oxygen-induced retinopathy (OIR) model. VEGFA induced phosphorylation of Pak1 and its effector
cofilin in a manner that was dependent on time as well as p38MAPKβ (also known as MAPK11) in human
retinal microvascular endothelial cells (HRMVECs). Depletion of the levels of any of these molecules inhibited VEGFA-induced HRMVEC
F-actin stress fiber formation, migration, proliferation, sprouting and tube formation. In accordance with these observations,
hypoxia induced Pak1 and
cofilin phosphorylation with p38MAPKβ being downstream to Pak1 and upstream to
cofilin in mouse retina. Furthermore, Pak1 deficiency abolished
hypoxia-induced p38MAPKβ and
cofilin phosphorylation and abrogated
retinal endothelial cell proliferation, tip cell formation and neovascularization. In addition,
small interfering RNA (
siRNA)-mediated downregulation of p38MAPKβ or
cofilin levels in the wild-type mouse retina also diminished endothelial cell proliferation, tip cell formation and neovascularization. Taken together, these observations suggest that, although the p38MAPKβ-Pak1-cofilin axis is required for HRMVEC migration, proliferation, sprouting and tubulogenesis, Pak1-p38MAPKβ-cofilin signaling is also essential for
hypoxia-induced mouse
retinal endothelial cell proliferation, tip cell formation and neovascularization.