Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A _2B adenosine receptor signaling

Abstract

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.

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…It has also been shown to promote production of TGF-beta [58]. Recently, it has been demonstrated that adenosine, signaling via A 2B R, stimulates TGF-beta secretion from corpus cavernosum fibroblasts in an autocrine fashion, thereby promoting fibroblast proliferation and increased production of collagen [59]. This represents a common final pathway in hepatic and penile fibrosis.…”

Medical management of ischemic stuttering priapism: a contemporary review of the literature

“…[74][75][76] Theophylline, an adenosine receptor antagonist, has consequently been shown to inhibit these adenosine-induced erections. 74,79 These results suggest the possibility that another signaling pathway may represent a potential target for the future prevention and treatment of priapism.…”

Androgen Deprivation Induces Bladder Histological Abnormalities and Dysfunction via TGF-.BETA. in Orchiectomized Mature Rats

“…TGF-β 1 is a common profibrotic factor that mediates the pathologic process of fibrosis in multiple organs (Matsuoka and Tsukamoto 1990;Wen et al 2010;Lang et al 2011;Samarakoon et al 2012). Matsuoka and Tsukamoto (1990) found that TGF-β 1 plays critical role in pathogenetic role in alcoholic liver fibrogenesis by stimulation of hepatic lipocyte collagen production.…”

“…However the intermediate molecule and signaling pathway are unknown. Realizing that TGF-β 1 is a common profibrotic factor which mediates the pathologic process of fibrosis in multiple organs (Matsuoka and Tsukamoto 1990;Wen et al 2010;Lang et al 2011;Samarakoon et al 2012), we hypothesize that TGF-β 1 is responsible for androgen deprivation-induced fibrosis in bladder tissues. To test this hypothesis, firstly we measured the TGF-β 1 mRNA levels Androgen deprivation induced TGF-β production contributes to induction of pro-collagen I mRNA expression level.…”

“…RNase-free DNase (Invitrogen, CA, USA) was used to eliminate genomic DNA contamination. Transcript levels were quantified using real-time quantitative RT-PCR (Wen et al 2010). Cyber green was used for analysis of α 2 (I) procollagen, TGF-β 1 and β-actin using the following primers: α 2 (I) procollagen, forward, 5′-AGACAT GCTCAGCTTTGTGGATAC-3′ and reverse, 5′-CGTACTGAT CCCGATTGCAAAT 3′; TGF-β1, forward, 5′-CCCCACTGATAC GCCTGAGT-3′ and reverse, 5′-GCCCTGTATTCCGTCTCCTT-3′; β-actin, forward, 5′-GCTCTGGCTCCTAGCACCAT-3' and reverse, 5′-CCACCGATCCACACAGAGTAC-3′.…”