Disorganization of Elastin Matrix Mediates Erectile Dysfunction

描述（由申请人提供）：阴茎海绵体的外层，即图尼卡白蛋白层，富含弹性纤维，并具有响应血压力而扩张的能力，导致阴茎长度和直径增加。然而，图尼卡的可扩张性是有限的，最终海绵体内压（ICP）的初始升高沿着图尼卡白蛋白的反作用力激活了静脉流出的机械闭塞或“阻塞”。因此，阴茎小动脉和窦状隙扩张后的合并血液流入以及随后的静脉闭塞导致ICP持续升高和勃起。我们最近发现，Db/db小鼠，一种常见的II型糖尿病小鼠模型，具有静脉闭塞性疾病，其源于缺乏组织填充，部分原因是血管反应性改变与海绵体松弛能力受损一致。我们还发现这些小鼠由于纤维胶原和弹性蛋白的沉积改变而导致组织扩张性可能受损。弹性纤维在细胞外组装，由弹性蛋白和特定的微纤维蛋白组成。与大多数蛋白质不同，弹性蛋白的产生仅限于短暂的发育期，在胎儿生长期间开始，并在新生儿早期达到高峰。此后，弹性蛋白的产生迅速下降。到成熟时，弹性纤维的组装完成，并且新的弹性蛋白原（可溶性前体）的合成已经下降。然而，某些疾病，如肺动脉高压和肺气肿，其特征在于弹性蛋白的异常积累或不能响应于损伤重新启动弹性蛋白产生。还有一些疾病，如马凡氏综合征和拉克萨，是由支持弹性蛋白组织的基因突变引起的。在这个提议中，我们假设弹性蛋白沉积和纤维形成对于适当的勃起功能至关重要，并且这个过程在II型糖尿病小鼠中改变，导致静脉闭塞功能受损和勃起功能障碍。由于弹性蛋白降解也已知发生在吸烟和/或衰老后的组织中，因此从该提案中获得的这一知识也可能对与这些风险因素相关的勃起功能障碍产生影响。公共卫生相关性：勃起依赖于阴茎的扩张能力，而扩张能力是由图尼卡白膜和窦状隙中丰富的弹性蛋白实现的。我们推测，弹性蛋白含量和弹性纤维组织的破坏有助于与II型糖尿病相关的勃起功能障碍。

DESCRIPTION (provided by applicant): The outer layer of the corpus cavernosum, the tunica albuginea, is rich in elastic fibers and has the capacity to expand in response to the force of blood pressure, resulting in an increased length and diameter of the penis. However, the expandability of the tunica is finite, and ultimately the initial rise in intracavernosal pressure (ICP) along with the opposing force of the tunica albuginea activates a mechanical occlusion or "sandwiching" of the venous outflow. Thus, the combined inflow of blood following penile arteriole and sinusoidal dilation, as well as subsequent veno-occlusion, result in maintained elevation of ICP and erection. We recently found that Db/db mice, a common mouse model of type II diabetes, have a veno-occlusive disorder that stems from a lack of tissue filling due, in part, to altered vasoreactivity consistent with impaired cavernosal relaxant ability. We also showed that these mice have may impairment in tissue distensability resulting from altered deposition of fibrillar collagen and elastin. Elastic fibers are assembled extracellularly and are comprised of elastin and specific microfibrillar proteins. Unlike most proteins, elastin production is limited to a brief period of development, beginning during fetal growth and peaking during early neonatal periods. Thereafter, elastin production declines rapidly. By maturity, assembly of elastic fibers is complete, and synthesis of new tropoelastin, the soluble precursor, has declined. Certain diseases, however, such as pulmonary hypertension and emphysema, are characterized by an abnormal accumulation of elastin or by an inability to re-initiate elastin production in response to injury. Still other diseases, such as Marfan's syndrome and cutis laxa, arise from mutations in genes that support elastin organization. In this proposal, we hypothesize that elastin deposition and fiber formation is critical for proper erectile function and that this process is altered in type II diabetic mice, resulting in impaired veno-occlusive function and erectile dysfunction. As elastin degradation is also known to occur in tissue following smoking and/or aging, this knowledge gained from this proposal may also have implications for erectile dysfunction associated with these risk factors as well. PUBLIC HEALTH RELEVANCE: Erection is dependent on distensability of the penis which is enabled by the abundance of elastin in the tunica albuginea and sinusoids. We hypothesize that disruptions in elastin content and elastic fiber organization contribute to erectile dysfunction associated with type II diabetes.