Disorganization of Elastin Matrix Mediates Erectile Dysfunction

描述(申请人提供)：阴茎海绵体的外层，白膜，富有弹性纤维，有能力随着血压的力量而膨胀，导致阴茎的长度和直径增加。然而，白膜的扩张性是有限的，最终，海绵体内压的最初升高以及白膜的反作用力会激活静脉流出的机械闭塞或“夹层”。因此，阴茎小动脉和静脉窦扩张后的血液流入，以及随后的静脉闭塞，导致持续的颅内压升高和勃起。我们最近发现，db/db小鼠，一种常见的II型糖尿病小鼠模型，有一种静脉闭塞障碍，源于缺乏组织充盈，部分原因是与海绵体松弛能力受损的血管反应性改变一致。我们还表明，这些小鼠可能由于纤维胶原和弹性蛋白沉积的改变而导致组织扩张性受损。弹性纤维是在细胞外组装的，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阶段，从胎儿发育开始，在新生儿早期达到顶峰。此后，弹性蛋白的产量迅速下降。到成熟时，弹性纤维的组装已经完成，新的原弹性蛋白--可溶的前体--的合成已经下降。然而，某些疾病，如肺动脉高压和肺气肿，其特征是弹性蛋白异常堆积或无法重新启动弹性蛋白的产生，以应对损伤。还有其他疾病，如马凡氏综合症和皮肤松弛，是由支持弹性蛋白组织的基因突变引起的。在这项建议中，我们假设弹性蛋白沉积和纤维形成对正常的勃起功能至关重要，并且这一过程在II型糖尿病小鼠中发生改变，导致静脉闭塞功能受损和勃起功能障碍。由于已知的弹性蛋白降解也发生在吸烟和/或衰老后的组织中，从这一建议中获得的知识也可能对与这些危险因素相关的勃起功能障碍产生影响。与公共卫生相关：勃起依赖于阴茎的可扩张性，这是由白膜和血窦中丰富的弹性蛋白实现的。我们假设，弹性蛋白含量和弹性纤维组织的紊乱导致了与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.