<div>The expression and activity of COX-1 in HUVEC regulates the formation of
tubular structures induced by cancer
cells (Tsujii et al., 1998).
LL-37, the only cathelicidin protein expressed by humans, upregulated in
breast, ovarian and lung tumors (Larrick et al., 1995; Coffelt et al.,
2009; Weber et al., 2009; Haussen et al., 2008).The Cathelicidin LL-37
can induce a proangiogenic response via cPLA2-COX-1-PGE2-EP3 Signaling
in human ECs, which is suppressed by aspirin in a manner of inhibiting
COX-1 in vivo (Salvado et al., 2013) (Figure 2). Activation of PGE2/EP3
axis promotes sprouting angiogenesis by suppression of protein kinase A
(PKA)/p-S675- β-catenin/Notch signaling in ECs (Chen et al., 2017).
Moreover, fibroblast growth factor-1 and fibroblast growth factor-2 are
the first two discovered polypeptides showing proangiogenic effects
(Thomas et al., 1985; Esch et al., 1985). FGFR1 (Fibroblast Growth
Factor Receptor 1) pathway in microvascular endothelial cells can be
activated by EP3 receptor signal mediation (Federica et al., 2008). The
2,5-dihydroxyphenylic acids (Gentisic Acid), a metabolite of Aspirin, is
a powerful fibroblast growth factor Inhibitor (Grootveld et al., 1998;
Fernández et al., 2010). Furthmore, angiogenic effects of PGE2 are
mediated by up-regulation of the C-X-C chemokine receptor type 4 (CXCR4)
and CXCR4 expression can be inhibited by aspirin in HMECs (Rosalba et
al., 2003). However, it warrants further research to verify the
downstream of cPLA2-COX-1-PGE2-EP3 signalling transduction when aspirin
antiangiogenesis.</div><div><b>Figure 2 Shown some signalling pathways that are targets of
aspirin to inhibit tumor angiogenesis.</b>However, it warrants further study
to verify the downstream of signalling transduction in these pathways.</div><div>It has been demonstrated that COX-2 in ECs is vital in regulating
angiogenesis, and the microvessel density relate to the level of COX-2
expression (Jones et al., 1999;
Kazuhiko et al., 2000). Moreover, in the sponge implanted mouse model,
COX-2 mediated prostaglandins can up-regulate the expression of VEGF
mRNA (Yoshida et al., 2003).</div><div>However, aspirin effectively inhibits COX-1 activity at a
pharmacological concentration, but has a weaker active to block COX-2
activity (Meade et al., 1993; Mitchell et al., 1993). In fact, it has
been demonstrated that salicylate inhibits Cyclooxygenase-2
transcription induced by IL-1β or phorbol 12-myristate 13-acetate by
blocking C/Enhancer-binding Protein β binding to its cognate site on
Cyclooxygenase-2 promoter (Michael et al., 2001). Furthermore, aspirin
and sodium salicylate at pharmacological concertration blocked COX-2
protein expresion induced by cancer and VEGF (Shtivelband et al., 2003)
(Figure 2). COX-2 protein levels in HUVECs, inducing by PMA (Porbolol
12-myristate 13-acetate), inhibited by Aspirin and sodium salicylate in
the manner of concentration-dependent
(Xu et al., 1999). Therefore, aspirin may inhibit COX-1 activity and
COX-2 transcription to regulate angiogenesis.</div>