Natriuretic peptide clearance receptor ligand (C-ANP4-23) attenuates angiogenesis in a murine sponge implant model

Natriuretic peptide receptor-C activation by the synthetic ligand C-ANP-(4-23,) a specific agonist for this receptor, has been shown to inhibit key events of the angiogenic cascade, such as migration, proliferation and vascular endothelial growth factor (VEGF) production. In the present study we investigated whether C-ANP(4-23) could also inhibit angiogenesis in the sponge model in vivo. To this end, we evaluated the effects of C-ANP(4-23) on inflammatory and angiogenic components of the fibrovascular tissue induced by polyether polyurethane sponge implants in mice. Measurements of the haemoglobin content (g/mg wet tissue) and blood flow (laser Doppler perfusion imaging) of the implants, used as an index of vascularization, revealed that single (200ng) or multiple (200ng/day, 5days) doses of C-ANP(4-23) reduced angiogenesis in the implants relative to the phosphate-buffered saline-treated group. The peptide exerted an inhibitory effect on nitric oxide production (nitrite levels) and had a dual effect on VEGF levels, depending on the number of doses (i.e. stimulation at 4days after one dose; inhibition at 7days after five doses). Histological analysis corroborated the biochemical and functional parameters indicative of inhibition of neovascularization (decreased vessel number) by C-ANP(4-23). The peptide failed to modulate inflammation in our system. The inhibitory effect of C-ANP(4-23) on the angiogenic component of the fibrovascular tissue induced by the synthetic matrix extends the range of the its actions and may indicate its therapeutic potential in controlling angiogenesis in fibroproliferative diseases.