Abstract
Nitric oxide (NO) is a proangiogenic factor acting through the soluble guanylate cyclase (sGC) pathway. However, angiogenic growth increases energy demand, which may be hampered by NO inhibition of cytochrome c oxidase (CcO). Then, NO activity would be the balanced result of sGC activation (pro-angiogenic) and CcO inhibition (anti-angiogenic). NO activity in a rat and eNOS−/− mice aortic ring angiogenic model and in a tube formation assay (human aortic endothelial cells) were analyzed in parallel with mitochondrial O2 consumption. Studies were performed with NO donor (DETA-NO), sGC inhibitor (ODQ), and NOS or nNOS inhibitors (L-NAME or SMTC, respectively). Experiments were performed under different O2 concentrations (0–21%). Key findings were: (i) eNOS-derived NO inhibits angiogenic growth by a mechanism independent on sGC pathway and related to inhibition of mitochondrial O2 consumption; (ii) NO inhibition of the angiogenic growth is more evident in hypoxic vessels; (iii) in the absence of eNOS-derived NO, the modulation of angiogenic growth, related to hypoxia, disappears. Therefore, NO, but not lower O2 levels, decreases the angiogenic response in hypoxia through competitive inhibition of CcO. This anti-angiogenic activity could be a promising target to impair pathological angiogenesis in hypoxic conditions, as it occurs in tumors or ischemic diseases.
Highlights
Blood vessels possess the capacity to rapidly form new sprouts in response to physiological demands or under pathological conditions requiring blood supply, as hypoxia or tumor growth
In order to investigate the activity of exogenous Nitric oxide (NO) in the angiogenic process, rat aortic rings were incubated for 6 days in Matrigel® and endothelial cell medium enriched with growth factors and in the absence or presence of different concentrations of DETA-NO, a NO donor
The role of NO on the angiogenic process would be the balanced result of soluble guanylate cyclase (sGC) activity and cellular energy availability; the latter dependent on cytochrome c oxidase (CcO) function
Summary
Blood vessels possess the capacity to rapidly form new sprouts (sprouting angiogenesis) in response to physiological demands or under pathological conditions requiring blood supply, as hypoxia or tumor growth. The surrounding tissues needed for O2 and nutrients incites the production of growth factors, such as the vascular endothelial growth factor (VEGF), which acts as pro-angiogenic stimuli. The thin layer of ECs that lines the inner surface of blood vessels can rapidly switch from a quiescent to a highly proliferative state required for angiogenesis [1], and this change allows for new vessels to sprout from parental vessels. The EC exposed to the highest VEGF level, becomes the “tip cell”. The sprout elongates by multiplying the number of “stalk cells” immediately behind the tip cell. This process involves some tightly coordinated events, including the degradation of the extracellular matrix, migration and proliferation of ECs, smooth muscle cells and pericytes to assemble new vessels [2]
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