Reactive Oxygen Species in Physiologic and Pathologic Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 76

Fig. 2 Signaling pathways regulated by NADPH oxidase-derived ROS leading to angiogenesis.
Growth factor binds to its receptor leading to translocation of GTPase Rac 1 into plasma
membrane, stimulating ROS production by NADPH oxidases. These ROS inactivate negatively
regulating protein tyrosine phosphatases (PTP-SH ? PTP-SOH) enhancing receptor autophos-
phorylation. Multiple signaling pathways leading to angiogenesis are activated
VEGFR2 after VEGF stimulation to inhibit VEGF-induced VEGFR2 auto-
phosphorylation and subsequent endothelial cell migration and proliferation
[ 89 - 91 ]. Thus PTP inactivation by ROS allows increased VEGF signaling.
ROS also activate downstream signaling pathways. Mitogen activated protein
kinases (MAP kinases), which are important to cell proliferation and migration, are
redox sensitive. Hydrogen peroxide activated p38 MAPK in endothelial cells,
leading to actin reorganization, stress fiber formation, and vinculin recruitment to
focal adhesions [ 92 ]. Akt plays a key role in cell survival. Hydrogen peroxide
stimulated Akt in smooth muscle cells, and angiopoietin-1 enhanced Akt phos-
phorylation and angiogenesis via NADPH oxidase ROS production in endothelial
cells [ 93 , 94 ]. Akt activation could occur either through enhanced receptor tyrosine
kinase signaling through PTP inactivation, or ROS may inactivate the phosphatase
PTEN which is a negative regulator of PI3K that is upstream of Akt [ 95 ]. Addi-
tionally, ROS may act more directly through Rac1 to decrease cell-cell adhesion
and promote cytoskeletal reorganization required for endothelial cell migration
[ 96 , 97 ].