Alprostadil suppresses angiogenesis in vitro and in vivo in the murine Matrigel plug assay.
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 alpha-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.
Cattaneo
Maria Grazia
MG
Department of Pharmacology, University of Milano, Via Vanvitelli, 32, 20129 Milano, Italy. Schwarz Pharma S.p.A., Via Gadames, 57, 20151 Milano, Italy.
Pola
Sandra
S
Dehò
Valeria
V
Sanguini
Anna Maria
AM
Vicentini
Lucia Maria
LM
D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003505:Cyclodextrins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007797:Laminin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011509:Proteoglycans / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047391:alpha-Cyclodextrins
D003505:Cyclodextrins; D004338:Drug Combinations; D007797:Laminin; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; D011509:Proteoglycans; C545645:Ptger2 protein, mouse; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D047391:alpha-Cyclodextrins; C059485:matrigel; D003094:Collagen; D000242:Cyclic AMP; D000527:Alprostadil; C032613:alpha-cyclodextrin