Neoangiogenesis is a response to retinal hypoxia that is inhibited by somatostatin (SRIF) through its subtype 2 receptor (sst2). Using a mouse model of hypoxia-induced retinopathy, we investigated whether inhibition of adenylyl cyclase (AC) is involved in SRIF anti-angiogenic actions. Hypoxia increased AC responsiveness in wild type (WT) retinas and in retinas lacking sst2, but not in sst2-overexpressing retinas. Hypoxia also altered AC isoform expression with different patterns depending on sst2 expression level. The AC VII isoform mRNA and protein resulted the most affected. Indeed, in hypoxia AC VII expression was enhanced in WT retinas and it was further increased in sst2-lacking retinas, whereas in sst2 overexpressing retinas the increase of AC VII was lower than in WT retinas. These data suggest an involvement of AC/cAMP in mediating both hypoxia-evoked retinal neoangiogenesis and SRIF protective actions. The AC VII isoform is a candidate to a main role in these mechanisms.