Priapism is a condition of persistent penile erection in the absence of sexual excitation. Of men with
sickle cell disease (SCD), 40% display
priapism. The disorder is a dangerous and urgent condition, given its association with penile
fibrosis and eventual
erectile dysfunction. Current strategies to prevent its progression are poor because of a lack of fundamental understanding of the molecular mechanisms for penile
fibrosis in
priapism. Here we demonstrate that increased
adenosine is a novel causative factor contributing to penile
fibrosis in two independent animal models of
priapism,
adenosine deaminase (ADA)-deficient mice and SCD transgenic mice. An important finding is that chronic reduction of
adenosine by ADA
enzyme therapy successfully attenuated penile
fibrosis in both mouse models, indicating an essential role of increased
adenosine in penile
fibrosis and a novel therapeutic possibility for this serious complication. Subsequently, we identified that both mice models share a similar fibrotic gene expression profile in penile tissue (including
procollagen I,
TGF-beta(1), and
plasminogen activator inhibitor-1 mRNA), suggesting that they share similar signaling pathways for progression to penile
fibrosis. Thus, in an effort to decipher specific cell types and underlying mechanism responsible for
adenosine-mediated penile
fibrosis, we purified corpus cavernosal fibroblast cells (CCFCs), the major cell type involved in this process, from wild-type mice. Quantitative RT-PCR showed that the major receptor expressed in these cells is the
adenosine receptor A(2B)R. Based on this fact, we further purified CCFCs from A(2B)R-deficient mice and demonstrated that A(2B)R is essential for excess
adenosine-mediated penile
fibrosis. Finally, we revealed that
TGF-beta functions downstream of the A(2B)R to increase CCFC
collagen secretion and proliferation. Overall, our studies identify an essential role of increased
adenosine in the pathogenesis of penile
fibrosis via A(2B)R signaling and offer a potential target for prevention and treatment of penile
fibrosis, a dangerous complication seen in
priapism.-Wen, J., Jiang, X., Dai, Y., Zhang, Y., Tang, Y., Sun, H., Mi, T., Phatarpekar, P. V., Kellems, R. E., Blackburn, M. R., Xia, Y. Increased
adenosine contributes to penile
fibrosis, a dangerous feature of
priapism, via A(2B)
adenosine receptor signaling.