Medical School of Chinese PLA, Beijing, China.
Senior Department of Otorhinolaryngology Head and Neck Surgery, The 6th Medical Center, Chinese PLA General Hospital, Beijing, China.
Curr Neurovasc Res. 2024;21(3):274-285. doi: 10.2174/0115672026320884240620070951.
Adherens junction in the blood-labyrinth barrier is largely unexplored because it is traditionally thought to be less important than the tight junction. Since increasing evidence indicates that it actually functions upstream of tight junction adherens junction may potentially be a better target for ameliorating the leakage of the blood-labyrinth barrier under pathological conditions such as acoustic trauma.
This study was conducted to investigate the pathogenesis of the disruption of adherens junction after acoustic trauma and explore potential therapeutic targets.
Critical targets that regulated the disruption of adherens junction were investigated by techniques such as immunofluorescence and Western blotting in C57BL/6J mice.
Upregulation of Vascular Endothelial Growth Factor (VEGF) and downregulation of Pigment Epithelium-derived Factor (PEDF) coactivated VEGF-PEDF/VEGF receptor 2 (VEGFR2) signaling pathway in the stria vascularis after noise exposure. Downstream effector Src kinase was then activated to degrade VE-cadherin and dissociate adherens junction, which led to the leakage of the blood-labyrinth barrier. By inhibiting VEGFR2 or Src kinase, VE-cadherin degradation and blood-labyrinth barrier leakage could be attenuated, but Src kinase represented a better target to ameliorate blood-labyrinth barrier leakage as inhibiting it would not interfere with vascular endothelium repair, neurotrophy and pericytes proliferation mediated by upstream VEGFR2.
Src kinase may represent a promising target to relieve noise-induced disruption of adherens junction and hyperpermeability of the blood-labyrinth barrier.
血迷路屏障中的黏附连接在很大程度上尚未被探索，因为传统上认为它不如紧密连接重要。由于越来越多的证据表明，它实际上在紧密连接之前发挥作用，因此黏附连接可能是改善病理条件下（如声创伤）血迷路屏障渗漏的更好靶点。
本研究旨在探讨声创伤后黏附连接破坏的发病机制，并探索潜在的治疗靶点。
通过免疫荧光和 Western blot 等技术，在 C57BL/6J 小鼠中研究了调节黏附连接破坏的关键靶点。
噪声暴露后，血管内皮生长因子 (VEGF) 的上调和色素上皮衍生因子 (PEDF) 的下调共同激活了血管纹中的 VEGF-PEDF/VEGF 受体 2 (VEGFR2) 信号通路。随后，下游效应物Src 激酶被激活，降解 VE-钙黏蛋白并解离黏附连接，导致血迷路屏障渗漏。通过抑制 VEGFR2 或 Src 激酶，可以减轻 VE-钙黏蛋白降解和血迷路屏障渗漏，但 Src 激酶作为改善血迷路屏障渗漏的靶点更好，因为抑制它不会干扰由上游 VEGFR2 介导的血管内皮修复、神经营养和周细胞增殖。
Src 激酶可能是缓解噪声诱导的黏附连接破坏和血迷路屏障通透性增加的有前途的靶点。
