Sturny Mikael, Anguenot Léa, Costa-Fraga Fabiana P, Bragina Maiia E, Lima Augusto Martins, da Silva Rafaela F, Fraga-Silva Rodrigo A, Stergiopulos Nikolaos
Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
J Sex Med. 2021 May;18(5):875-888. doi: 10.1016/j.jsxm.2021.02.004. Epub 2021 Apr 15.
An increased fibrosis of the corpora cavernosa is a prevalent process that underlies most cases of erectile dysfunction. Apelin, an endogenous circulating peptide, has been documented as an important effector on cardiovascular homeostasis, controlling vascular function and reducing fibrosis in multiple pathological conditions. Recently, initial studies have shown that Apelin, acting through the APJ receptor, also modulates penile erection, however, the role of this system on penile structure and intracorporal collagen remodeling has not been investigated yet.
Here we sought to investigate the effect of chronic Apelin treatment on the corpus cavernosum structure of hyperchOlesterolemic mice.
Apolipoprotein gene-deleted (ApoE) mice were fed with a Western diet for 11 weeks and received Apelin-13 (2 mg/kg/day) or vehicle during the last 3 weeks. Penile samples were obtained for histological and biochemical analyses to assess the intracorporal collagen content and key proteins expression. Furthermore, the effect of Apelin-13 was evaluated in cultured NIH3T3 mouse fibroblasts stimulated with TGF-β.
Local expression of Apelin-13 in mouse corpus cavernosum and its protective effect against fibrosis.
Apelin and APJ receptor were expressed (gene and protein) within the corpus cavernosum of ApoE mice, indicating a local modulation of the Apelin system. Interestingly, 3 weeks of Apelin-13 treatment strongly reduced intracavernosal collagen content. In addition, Apelin-13 enhanced total matrix metalloproteinase (MMP) activity in the mice penis, which was associated with an increased protein expression of MMP-1, MMP-3, MMP-8, and MMP-9, while tissue inhibitor of metalloproteinase were unaltered. These beneficial actions were not associated with changes in nNOS or eNOS protein expression, intracavernosal reactive oxygen species content, or atherosclerotic plaque deposition. Additionally, in cultured fibroblast, Apelin-13 inhibited TGF-β-induced fibroblast to myofibroblast differentiation and collagen production, possibly through the activation of ERK1/2 kinase.
These results point out Apelin/APJ system as a potential target to treat intracavernosal fibrosis-related disorders.
STRENGTH & LIMITATIONS: These results provide the first evidence of the Apelin system's positive role on erectile tissue structure/remodeling. Nevertheless, additional functional study addressing erectile response would bring extended validation regarding the relevance of such effect.
These results suggest a local modulation of the Apelin system within the corpus cavernosum. Remarkably, Apelin-13 reduced intracavernosal fibrosis in hypercholesterolemic mice by: (i) enhancing MMPs expression and activity; and (ii) inhibiting fibroblast differentiation into myofibroblast. Altogether, these results suggest an essential protective role of Apelin, indicating Apelin/APJ system as a promising candidate for the development of fibrosis-associated erectile dysfunction treatments. Sturny M, Anguenot L Costa-Fraga FP, et al. Apelin-13 Protects Corpus Cavernosum Against Fibrosis Induced by High-Fat Diet in an MMP-Dependent Mechanism. J Sex Med 2021;18:875-888.
海绵体纤维化增加是一个普遍存在的过程，是大多数勃起功能障碍病例的基础。Apelin是一种内源性循环肽，已被证明是心血管稳态的重要调节因子，在多种病理状态下控制血管功能并减少纤维化。最近，初步研究表明，Apelin通过APJ受体发挥作用，也能调节阴茎勃起，然而，该系统对阴茎结构和海绵体内胶原蛋白重塑的作用尚未得到研究。
在此，我们试图研究慢性Apelin治疗对高胆固醇血症小鼠海绵体结构的影响。
给载脂蛋白基因缺失（ApoE）小鼠喂食西式饮食11周，并在最后3周给予Apelin-13（2mg/kg/天）或赋形剂。获取阴茎样本进行组织学和生化分析，以评估海绵体内胶原蛋白含量和关键蛋白表达。此外，在经转化生长因子-β（TGF-β）刺激的培养NIH3T3小鼠成纤维细胞中评估Apelin-13的作用。
Apelin-13在小鼠海绵体中的局部表达及其对纤维化的保护作用。
Apelin和APJ受体在ApoE小鼠的海绵体内表达（基因和蛋白），表明Apelin系统存在局部调节。有趣的是，3周的Apelin-13治疗显著降低了海绵体内胶原蛋白含量。此外，Apelin-13增强了小鼠阴茎中的总基质金属蛋白酶（MMP）活性，这与MMP-1、MMP-3、MMP-8和MMP-9的蛋白表达增加有关，而金属蛋白酶组织抑制剂未发生改变。这些有益作用与神经元型一氧化氮合酶（nNOS）或内皮型一氧化氮合酶（eNOS）蛋白表达、海绵体内活性氧含量或动脉粥样硬化斑块沉积的变化无关。此外，在培养的成纤维细胞中，Apelin-13可能通过激活细胞外信号调节激酶1/2（ERK1/2）激酶抑制TGF-β诱导的成纤维细胞向肌成纤维细胞分化和胶原蛋白产生。
这些结果指出Apelin/APJ系统是治疗海绵体内纤维化相关疾病的潜在靶点。
这些结果首次证明了Apelin系统对勃起组织结构/重塑的积极作用。然而，关于勃起反应的额外功能研究将为这种作用的相关性带来进一步验证。
这些结果表明海绵体内存在Apelin系统的局部调节。值得注意的是，Apelin-13通过以下方式减少高胆固醇血症小鼠的海绵体内纤维化：（i）增强MMPs的表达和活性；（ii）抑制成纤维细胞向肌成纤维细胞分化。总之，这些结果表明Apelin具有重要的保护作用，表明Apelin/APJ系统是开发与纤维化相关的勃起功能障碍治疗方法的有希望的候选者。斯特尔尼M、安格诺特L、科斯塔-弗拉加FP等。Apelin-13通过MMP依赖性机制保护海绵体免受高脂饮食诱导的纤维化。《性医学杂志》2021年；18：875-888。
