Alprostadil suppresses angiogenesis in vitro and in vivo in the murine Matrigel plug assay

Abstract

1. Prostaglandin E 1 (PGE 1, alprostadil) is used as a vasodilator for the treatment of peripheral vascular diseases. 2. Previous reports suggested a pro-angiogenic effect for PGE 1. 3. We studied the in vitro and in vivo effect of PGE 1, complexed with α-cyclodextrin, on the angiogenic process. Contrary to what was expected, we found that, in human umbilical vein endothelial cells (HUVECs), PGE 1 inhibited proliferation, migration and capillary-like structure formation in Matrigel. 4. By RT-PCR studies, the expression of the EP 2 and EP 3 subtypes of the PG receptor was detected in HUVECs. 5. PGE 1 alone stimulated adenylate cyclase activity at micromolar concentrations, while at nanomolar concentrations potentiated the forskolin-induced cAMP accumulation. 6. 8-Bromoadenosine-3′:5′-cyclic monophosphate (Br-cAMP) mimicked the inhibitory effect of PGE 1 on endothelial cell growth, motility and tube formation. 7. Sulprostone, an agonist at the EP 3 subtype of PG receptors, mimicked the in vitro anti-angiogenic effects of PGE 1, while butaprost, an EP 2 receptor agonist, had no effect. 8. Finally, in the plug assay model of angiogenesis in mice, PGE 1 showed a strong inhibitory effect on Matrigel neovascularization. 9. Thus, PGE 1 possesses strong anti-angiogenic activity in vitro and in vivo.