Fig. 4

The VEGF-A/VEGFR-2 signaling pathway promotes angiogenesis in IH. VEGF-A promotes angiogenesis by activating the VEGFR-2 receptor in HemECs by triggering multiple downstream signaling pathways, including microvascular permeability, HemEC proliferation, migration, and survival. Activation of VEGFR-2 in HemECs triggers multiple downstream signals that promote angiogenesis. These pathways are as follows: (1) VEGFR-2 activates mitogen-activated protein/Ras/Raf1/ERK/MEK signaling pathways, which promote HemEC proliferation and thus promote angiogenesis. (2) The activation of the PI3K/serine-threonine protein kinase/Akt signaling pathway by VEGFR-2 promotes cell survival. VEGFR-2 also activates the Akt/mTOR/HIF-1/Gult-1/Glucose-1 signaling pathway and increases glycolysis to promote HemEC proliferation and thus promote angiogenesis. PI3K/Akt activation can promote the expression of Bcl-2 and play an anti-apoptotic role to promote cell survival. (3) VEGFR-2 can directly promote angiogenesis by activating the MKK/p38/MAPK/HSP27 signaling pathway and affecting intracellular actin recombination. (4) The VEGFR-2 receptor directly activates FAK/Paxillin to promote cell migration and thus generate neovascularization. These signaling pathways play different cellular biological functions but also have synergistic effects on each other to promote the generation of neovascularization. Mechanistic target of rapamycin (mTOR), hypoxia-inducible factor-1 (HIF-1), mitogen-activated protein kinase kinase (MKK), heat shock protein 27 (HSP27)