2.4 Effect on Hypoxia stimulation and GLUT1 expression
Neoplasms have been usually described as hypoxic structures, inefficient of oxygen transportation, and bearing twisted irregular vascular networks (Vaupel, 2004). Hypoxia-reoxygenation (HR), a major driver for tumor angiogenesis, stimulates proliferation of ECs via several signaling pathways including VEGF and transforming growth factor (TGFβ1) (Khaidakov et al., 2011; Hu et al., 2008). Moreover, overexpression of TGFβ-R1 shows angiostatic effect, while blocking TGFβ-R1 can facilitate VEGF-mediated capillary formation and activation of genes related to angiogenesis (Liu et al., 2009). Aspirin effectively inhibits the angiogenic response involved in HR-mediated TGFβ1 mRNA transcription and TGFβ1-R1 upregulating, thereby inhibiting HR-stimulated tube formation in HUVECs (Khaidakov et al., 2011). In addition, aspirin can inhibit LOX-1-NADPH oxidase pathway in HUVECs to suppress HR-induced tube formation (Khaidakov et al., 2010).
Glucose transporter 1 (GLUT1) is the main route to uptake glucose in ECs (Goveia et al., 2014). The expression of GLUT1 is promoted in ECs by hypoxia, and the high expression of GLUT1 is related to neoplasm angiogenesis (Zapata-Morales et al., 2014; Semaan et al., 2011). In the process of switching from a quiescent state to angiogenic phenotype, glycolysis provides the essential energy and promotes sprouting of blood vessels during tumor-induced angiogenesis (Rivera et al., 2014). Interesting, aspirin can not only inhibit the expression level of GLUT1 mRNA and protein resulting in impaired glucose uptake ability, but also inhibit the intracellular lactate synthesis and ATP of SEND cells (rat vascular endothelial cell line) (Hu et al., 2014 ). Moreover,taking high-dose aspirin, even reaching 90 mM, does not produce side effects that interfere with glycolysis and glucose uptake in human erythrocytes (Worathumrong et al., 1975). Thus, aspirin inhibits the sprouting of blood vessels through regulating the expression level of GLUT1 and inhibiting lactate synthesis. However, it warrants further study to clarify the detailed mechanisms of aspirin in these phenomenon.
2.5 Effect onrenin-angiotensin system
The renin-angiotensin system (RAS) is involved in a coordinated hormone cascade that regulates fluid-electrolyte balance and arterial pressure by controlling cardiovascular, adrenal and renal functions (Peach et al., 1997). Some studies suggest that angiotensin II (Ang II) in low concentrations can induce angiogenesis by activating angiotensin type 1 receptor (AT1R) and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (Skultetyova et al., 2007; Ushio-Fukai et al., 2006; Hu et al., 2007). MAP kinase activation is the downstream of NADPH oxidase, and inhibition of p38 and p44/42 MAP kinase can reduce angiogenesis (Hu et al., 2007; Seeger et al., 2010). Moreover, it has been noted that suppression of bradykinin degradation and angiotensin II(Ang II) synthesis in RAS can produce a net antiangiogenic state in tumorgenesis (Heffelfinger et al., 2007). Importantly, ASA and SA significantly reduce Ang II-induced expression of AT1R, VEGF, NADPH oxidase subtypes, p-p38 and p-p44/42 MAPKs in endothelial cells, and inhibite angiogenic effects of Ang II in capillary formation (Mitra et al., 2012). It warrants further study to research the effect of aspirin in renin-angiotensin system in clinical setting.