1 The angiogenic activity of four vasoactive peptides with a range of vasodilator and vasoconstrictor properties, i.e. vasoactive intestinal peptide (VIP), endothelin-1, endothelin-3 and angiotensin II, were investigated in a rat sponge model. Neovascularization was assessed by the 133Xe clearance technique and confirmed by histological studies. 2 Daily doses of the vasodilator peptide, VIP (1000 pmol), caused intense neovascularization, but a lower dose (10 pmol) produced no apparent effect. However, the lower dose of VIP, when given with a subthreshold dose of interleukin-1 alpha (0.3 pmol), produced an angiogenic response similar to that seen with the higher dose of VIP. The neovascular response induced by co-administration of VIP and interleukin-1 alpha was inhibited by simultaneous administration of 100 pmol VIP (10-28), a specific VIP receptor antagonist. 3 In contrast, daily doses of 10, 100 or 1000 pmol endothelin-3 (a mixed vasoconstrictor and vasodilator with more marked vasodilator activity) or of 100 or 1000 pmol endothelin-1 (also with mixed activity but with much more pronounced vasoconstrictor response) produced no apparent effect on sponge-induced angiogenesis. 4 The vasoconstrictor peptide, angiotensin II, in daily doses of 1000 pmol, caused an intense neovascularization like VIP but lower doses of angiotensin II (10 or 100 pmol) produced no apparent effect. The lowest dose of angiotensin II (10 pmol) when administered with the subthreshold dose of interleukin-1 alpha (0.3 pmol) had no effect on the basal neovascular response in the sponges. The angiotensin II-induced neovascular response was inhibited by co-administration of 100 nmol of the specific AT1 receptor antagonist, losartan, but not by the AT2 receptor antagonist, PD 123319. 5 These data show that VIP and angiotensin II possess angiogenic activity. However, endothelin-1 and endothelin-3 had no activity at the doses used. Thus the angiogenic response is not related to local vasoconstriction or vasodilatation in the sponges. The blockade of VIP- and angiotensin II-induced angiogenesis at the receptor level suggests that receptor modulation could provide a strategy for the management of angiogenic diseases.