Figure 2.

Schematic illustration of angiogenesis signaling pathways induced by OS. According to different responses to OS, two signal pathways of angiogenesis are covered, namely, the VEGF-dependent signaling pathway and VEGF-independent signaling pathway. In the VEGF-dependent pathway, ROS, NO, OxLDL, and OxPLs strongly stimulate the expression of HIF-1a and VEGF. Meanwhile, Poly I:C and LPS promote the expression of HIF-1α and VFGF by coupling with their specific receptors (TLR3 and TLR4). These further combine to the downstream receptor VEGFR-2 and facilitate angiogenesis by activating the HIF-1α/VFGF/VEGFR-2 signaling pathway in a VEGF-dependent manner. On the other hand, many mediators are involved in the VEGF-independent pathway, including CEP, LPS, MALP-2, PDGF, and ROS. CEP/yyMALP-2 initially couples to their receptors (TLR2/6), then sensitizes specific downstream targets (e.g., MyD88 and GM-CSF), and finally promotes angiogenesis. Meanwhile, ROS activate the P38 pathway via inducing the activation of ATM and ultimately result in angiogenesis. Besides, LPS is considered to induce angiogenesis through a TRAF6-mediated activation of NF-κB and JNK. As another soluble mediator, PDGF triggers PI3K/Akt and MAPK signaling by binding to its receptor and promotes neovascularization.