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Title: The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation
Authors: Freson, Kathleen
Hashimoto, Hitoshi
Thys, Chantal
Wittevrongel, Christine
Danloy, Sophie
Morita, Yoshiko
Shintani, Norihito
Tomiyama, Yoshiaki
Vermylen, Jozef
Hoylaerts, Marc
Baba, Akemichi
Van Geet, Christel # ×
Issue Date: Apr-2004
Series Title: Journal of Clinical Investigation vol:113 issue:6 pages:905-912
Abstract: The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide of the vasoactive intestinal peptide/secretin/glucagon superfamily. Studies in two related patients with a partial trisomy 18p revealed three copies of the PACAP gene and elevated PACAP concentrations in plasma. The patients suffer from severe mental retardation and have a bleeding tendency with mild thrombocytopenia, and their fibroblasts show increased PACAP mRNA levels. The PACAP receptor (vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor 1 [VPAC1]) in platelets and fibroblasts is coupled to adenylyl cyclase activation. Accordingly, we found increased basal cAMP levels in patients' platelets and fibroblasts, providing a basis for the reduced platelet aggregation in these patients. Megakaryocyte-specific transgenic overexpression of PACAP in mice correspondingly increased PACAP release from platelets, reduced platelet activation, and prolonged the tail bleeding time. In contrast, the PACAP antagonist PACAP(6-38) or a monoclonal PACAP antibody enhanced the collagen-induced aggregation of normal human platelets, and in PACAP knockout mice, an increased platelet sensitivity toward collagen was found. Thus, we found that PACAP modulates platelet function and demonstrated what we believe to be the first hemostatic defect associated with PACAP overexpression; our study suggests the therapeutic potential to manage arterial thrombosis or bleeding by administration of PACAP mimetics or inhibitors, respectively.
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
Pediatric Hematology & Oncology Section (-)
Faculty of Medicine - miscellaneous
× corresponding author
# (joint) last author

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