The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation.
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.
Freson
Kathleen
K
Center for Molecular and Vascular Biology, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium. kathleen.freson@med.kuleuven.ac.be
Hashimoto
Hitoshi
H
Thys
Chantal
C
Wittevrongel
Christine
C
Danloy
Sophie
S
Morita
Yoshiko
Y
Shintani
Norihito
N
Tomiyama
Yoshiaki
Y
Vermylen
Jos
J
Hoylaerts
Marc F
MF
Baba
Akemichi
A
Van Geet
Chris
C
D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002887:Chromosomes, Human, Pair 18; D002890:Chromosomes, Human, Pair 20; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D010375:Pedigree; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015539:Platelet Activation / Q000502:physiology*; D014178:Translocation, Genetic
C495401:ADCYAP1 protein, human; C495402:Adcyap1 protein, mouse; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D000262:Adenylyl Cyclases