Vactosertib, a Novel, Orally Bioavailable Activin Receptor-Like Kinase 5 Inhibitor, Promotes Regression of Fibrotic Plaques in a Rat Model of Peyronie’s Disease

Purpose: To examine the therapeutic effect of Vactosertib, a small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor (activin receptor-like kinase-5, ALK5), in an experimental model of Peyronie’s disease (PD) and determining anti-fibrotic mechanisms of Vactosertib in primary fibroblasts derived from human PD plaques. Materials and Methods: Male rats were randomly divided into three groups (n=6 per group); control rats without treatment; PD rats receiving vehicle; and PD rats receiving Vactosertib (10 mg/kg). PD-like plaques were induced by administering 100 μL of each of human fibrin and thrombin solutions into the tunica albuginea on days 0 and 5. Vactosertib was given orally five times a week for 2 weeks. On day 30, we performed electrical stimulation of the cavernous nerve to measure erectile function, and the penis was obtained for histological examination. Fibroblasts isolated from human PD plaques were used to determine the anti-fibrotic effects of Vactosertib in vitro. Results: Vactosertib induced significant regression of fibrotic plaques in PD rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-Smad2, which recovered erectile function. Vactosertib also abrogated TGF-β1-induced enhancement of extracellular matrix protein production and hydroxyproline content in PD fibroblasts in vitro by hindering the TGF-β1-induced Smad2/3 phosphorylation and nuclear translocation, and fibroblast-to-myofibroblast transdifferentiation. Conclusions: In view of the critical role of TGF-β and the Smad pathway in the pathogenesis of PD, inhibition of this pathway with an ALK5 inhibitor may represent a novel, targeted therapy for PD.研究目的：本研究旨在评估转化生长因子-β（transforming growth factor-β, TGF-β）I型受体（激活素受体样激酶-5, ALK5）小分子抑制剂Vactosertib在佩罗尼氏病（Peyronie’s disease, PD）实验模型中的治疗效果，并阐明其在人PD斑块来源的原代成纤维细胞（primary fibroblasts）中的抗纤维化作用机制。 材料与方法：将雄性大鼠随机分为三组（每组n=6）：未作任何处理的对照组大鼠、接受赋形剂给药的PD模型组大鼠、接受10 mg/kg Vactosertib给药的PD模型组大鼠。于第0天和第5天，向各组大鼠阴茎白膜内注射100 μL人纤维蛋白溶液与凝血酶溶液，以诱导PD样斑块形成。Vactosertib采用口服给药方式，每周5次，持续2周。于第30天，对大鼠海绵体神经进行电刺激以检测勃起功能，随后摘取阴茎组织用于组织学检查。此外，本研究采用从人PD斑块中分离得到的成纤维细胞，在体外探究Vactosertib的抗纤维化作用。 结果：体内实验显示，Vactosertib可通过减少炎症细胞浸润、降低磷酸化Smad2（phospho-Smad2）的表达，显著诱导PD模型大鼠的纤维化斑块消退，并恢复大鼠勃起功能。体外实验表明，Vactosertib可通过阻断TGF-β1诱导的Smad2/3磷酸化与核转位（nuclear translocation），抑制TGF-β1诱导的PD成纤维细胞外基质蛋白（extracellular matrix）生成增加及羟脯氨酸（hydroxyproline）含量升高，同时阻断成纤维细胞向肌成纤维细胞（myofibroblast）的转分化过程。 结论：鉴于TGF-β及Smad通路在PD发病机制中的关键作用，采用ALK5抑制剂阻断该通路或可为PD提供一种新型靶向治疗策略。