PACAP: a new player in thrombopoiesis

The complex mechanisms underlying megakaryopoiesis and platelet biogenesis are poorly understood, and identification of new molecules associated with these processes is highly welcome and often opens multiple new lines of investigation. This likely will be the case for the “new kid on the block” reported in this issue of Blood by Freson and colleagues: PACAP (pituitary adenylyl cyclase–activating peptide).

PACAP shares a high degree of homology with vasointestinal peptide (VIP), which was suggested nearly 20 years ago to play a negative role in platelet aggregation.¹  Both PACAP and VIP show high affinity for the VIP receptor, VPAC1, which is expressed in both platelets and megakaryocytes.² 

Clinically, it is known that trisomy of chromosome 18p results in platelet dysfunction and mild thrombocytopenia. Because PACAP is encoded on chromosome 18p, Freson and colleagues hypothesized that increased levels of this molecule (resulting from 3 copies of the PACAP gene) are responsible for the platelet dysfunction and thrombocytopenia observed in this syndrome. In another study, these same investigators demonstrated that megakaryocyte-specific transgenic overexpression of PACAP in mice led to decreased platelet activation.³ 

Freson and colleagues are extending their previous findings by providing evidence for the importance of the PACAP/VIP/VPAC1 axis in the regulation of platelet production. First, megakaryocytes from both patients and mice with excess copies of the PACAP gene were shown to exhibit signs of maturation arrest. Second, these investigators were able to stimulate megakaryopoiesis both in vitro and in vivo by inhibiting VPAC1 signaling with specific blocking antibodies. These observations demonstrate a clear negative regulatory role for PACAP in thrombopoiesis, which is likely secondary to decreased cAMP levels mediated by activation of VPAC1.

Perhaps an even more exciting component of this study is its investigation of potential therapeutic effects of inhibition of the PACAP/VIP/VPAC1 pathway. Using mice with congenital thrombocytopenia and rabbits with acquired thrombocytopenia, the authors demonstrate that infusion of a VPAC1-blocking antibody results in a significant (but temporary) elevation of the platelet count in a thrombopoietin-independent manner. Surprisingly, despite the potential pleiotropic effects of VPAC1 inhibition (VPAC1 is expressed in many other tissues including cells of the central nervous, gastrointestinal, and reproductive systems), no major adverse effects were observed.

Although this article successfully addresses the importance of the PACAP/VIP/VPAC1 axis, several mechanistic issues remain unclear. These include the downstream effects of VPAC1 inhibition that lead to raised platelet counts, the exact stages of platelet production in which VPAC1 is critical, and the potential consequences of VPAC1 inhibition in other systems if it is targeted for the treatment of thrombocytopenia. Future studies will likely answer these questions. This article is an excellent example of how an astute observation in the clinic can lead to an important mechanistic discovery, and is a further reminder of the important interface between clinical medicine and basic research.