title: Thrombopoietic effect of VPAC1 inhibition during megakaryopoiesis.
abstract: Megakaryocytes and platelets express the stimulatory G protein (Gs)-coupled VPAC1 receptor, for which the pituitary adenylyl cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are agonists. The neuropeptide PACAP and VPAC1 were previously found to negatively regulate megakaryopoiesis, and inhibition of their physiological pathway was found to have a thrombopoietic effect in conditions where megakaryopoiesis and thrombopoiesis were impaired, such as chemotherapy-induced thrombocytopenia and congenital thrombocytopenia. The present study explored the thrombopoietic effect of VPAC1 inhibition in a murine model of syngeneic bone marrow transplantation (BMT) and in passive immune thrombocytopenia. Treatment of donor mice with a neutralizing anti-VPAC1 antibody stimulated the initial, most critical recovery of the platelets in irradiated mice. In the passive immune thrombocytopenia model, we observed a thrombopoietic effect, resulting in a less severe platelet drop after induction of their removal in the spleen by an anti-platelet antibody. We concluded that inhibition of the physiological PACAP/VPAC1 pathway could stimulate in vivo megakaryopoiesis. This inhibition can be applied to attenuate thrombocytopenia in conditions where platelets are destroyed as the major pathogenetic mechanism, e.g. immune thrombocytopenia purpura, or need to be produced de novo, e.g. after irradiation and BMT.
authors.affiliation: Centre for Molecular and Vascular Biology ThromboGenics Department of Paediatrics, University of Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Peeters
authors.forename: Serena
authors.initials: S
authors.lastname: Loyen
authors.forename: Soetkin
authors.initials: S
authors.lastname: Van Kerckhoven
authors.forename: Katinka
authors.initials: K
authors.lastname: Stoffels
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.forename: Chris
authors.initials: C
authors.lastname: Van Geet
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008533:Megakaryocytes / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000503:physiopathology / Q000628:therapy; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000503:physiopathology / Q000628:therapy*; D034061:Thrombopoiesis / Q000502:physiology*; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I