Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Section of Urology and Renal Transplantation, Virginia Mason Medical Center, Seattle, Washington, USA.
Neurourol Urodyn. 2021 Mar;40(3):771-782. doi: 10.1002/nau.24635. Epub 2021 Mar 1.
Abnormal extracellular matrix (ECM) changes are correlated with stress urinary incontinence (SUI). The ECM components versican (Vcan) and hyaluronan (HA) play key roles in regulating tissue inflammation and maintaining connective tissue homeostasis. We analyzed the localization and expression of these ECM components in urethral and vaginal tissues from a rat model of urinary incontinence and from human clinical specimens.
Nulliparous rats underwent vaginal distension (VD), a rodent model of SUI, or a sham procedure. Tissues were harvested from six rats per group at days 1, 4, and 21 for immunohistochemistry and RNA expression analysis of ECM components. Periurethral vaginal samples from female patients with SUI were also examined.
High-intensity staining for Vcan was observed 1 day after procedure in both control and VD animals. This level of abundance persisted at day 4 in VD compared to control, with concurrent reduced messenger RNA (mRNA) expression of the Vcan-degrading enzymes ADAMTS5 and ADAMTS9 and reduced staining for the Vcan cleavage epitope DPEAAE. Abundance of HA was not different between VD and control, however mRNA expression of the HA synthase Has2 was significantly reduced in VD tissues at day 4. Abundant Vcan staining was observed in 60% of SUI patient samples, which was strongest in regions of disrupted elastin.
Reduction of Vcan-degrading enzymes and HA synthases at day 4 postsurgery indicates a potential delay in ECM turnover associated with SUI. Abundant Vcan is associated with inflammation and elastin fiber network disruption, warranting further investigation to determine its role in SUI pathogenesis.
异常细胞外基质（ECM）变化与压力性尿失禁（SUI）相关。ECM 成分 versican（Vcan）和透明质酸（HA）在调节组织炎症和维持结缔组织动态平衡方面发挥着关键作用。我们分析了尿失禁大鼠模型和人类临床标本中尿道和阴道组织中这些 ECM 成分的定位和表达。
未产大鼠接受阴道扩张（VD），即 SUI 的啮齿动物模型，或假手术。每组 6 只大鼠分别在第 1、4 和 21 天取组织，用于 ECM 成分的免疫组织化学和 RNA 表达分析。还检查了 SUI 女性患者的尿道旁阴道标本。
在对照和 VD 动物中，术后 1 天即可观察到 Vcan 的高强度染色。与对照相比，这种丰度在 VD 中持续到第 4 天，同时 Vcan 降解酶 ADAMTS5 和 ADAMTS9 的信使 RNA（mRNA）表达降低，并且 Vcan 切割表位 DPEAAE 的染色减少。然而，HA 的丰度在 VD 和对照之间没有差异，但是在 VD 组织中，HA 合酶 Has2 的 mRNA 表达在第 4 天显著降低。60%的 SUI 患者样本中观察到丰富的 Vcan 染色，在破坏的弹性纤维网络区域最强。
术后第 4 天 Vcan 降解酶和 HA 合酶的减少表明与 SUI 相关的 ECM 周转潜在延迟。丰富的 Vcan 与炎症和弹性纤维网络破坏有关，值得进一步研究以确定其在 SUI 发病机制中的作用。
