From patient to mouse to therapy: role of the neuropeptide pacap in platelet function and formation.

Megakaryopoiesis and platelet production are very complex processes, orchestrated by different growth factors, cytokines and transcription factors. It's only recently that a role was assigned for the pituitary adenylyl cyclase-activating peptide (PACAP) and the vasoactive intestinal peptide (VIP) via their common Gs-coupled receptor VPAC1 in this process. The basis for this idea originated from studies in two related patients with a partial trisomy 18p11 and therefore carrying 3 copies of the PACAP gene and elevated PACAP concentrations in their plasma which resulted in a bleeding tendency with thrombopathy and a mild thrombocytopenia. This platelet functional and formation defect could be phenocopied in transgenic megakaryocyte specific PACAP-overexpressing mice. The addition of PACAP or VIP to hematopoietic stem cells resulted in an decreased megakaryocyte maturation and DNA polyploidization. In contrast, mice subcutaneously injected with inhibitory anti-PACAP (PP1A4) or anti-VPAC1 (23A11) antibodies presented with increased platelet numbers. This last concept was the basis for the development of these antibodies for the treatment of different types of thrombocytopenia as the therapeutic value for these antibodies was established in mice with a low platelet count due to chemotherapy, anti-platelet antibodies, a congenital factor of after bone marrow transplantation. For all models, the addition of 23A11 or PP1A4 resulted in an increased platelet recovery compared to the control antibody. Further studies are needed to identify the downstream signal transduction components after VPAC1 stimulation in megakaryocytes and platelets.