Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Department of Anaesthesia, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China.
Gene. 2019 Apr 15;692:176-184. doi: 10.1016/j.gene.2019.01.009. Epub 2019 Jan 17.
Hepatopulmonary syndrome (HPS) is a serious complication in patients with advanced liver disease. The pathological pulmonary angiogenesis contributes to the progression of HPS. Importantly, directional collective migration of endothelial cells is a critical event for pathological angiogenesis. Previously, we have demonstrated that the over-expression of Cyclooxygenase-2 (COX-2) was an important factor in the experimental HPS. However, the role of COX-2 in the directional collective migration of human pulmonary microvascular endothelial cells (HPMVECs) is unclear. Our study aims to evaluate the potential effect of COX-2 in the directional collective migration of HPMVECs under the stimulation of HPS patient serum. In this study, 9 patients with stable liver cirrhosis were screened for presence of HPS. We confirmed that HPS patient serum dramatically promoted the directional collective migration and angiogenesis of HPMVECs, while the COX-2 selective antagonist parecoxib significantly inhibited the directional collective migration of HPMVEC under the stimulation of HPS patient serum. In addition, HPS patient serum significantly upregulated the phosphorylation of PKC and promoted the activation of Rac via COX-2/PGE2 signaling pathway. Notably, silencing PKC activation attenuated the directional collective migration of HPMVEC induced by HPS patient serum. In conclusion, these results indicate that PKC/Rac signaling induced by COX-2 modulates collective directional migration of HPMVEC during pathological pulmonary angiogenesis in HPS patients.
肝肺综合征（HPS）是一种严重的肝脏疾病并发症。肺部病理性血管生成导致 HPS 的进展。重要的是，内皮细胞的定向集体迁移是病理性血管生成的关键事件。以前，我们已经证明环氧化酶-2（COX-2）的过度表达是实验性 HPS 的一个重要因素。然而，COX-2 在人肺微血管内皮细胞（HPMVEC）的定向集体迁移中的作用尚不清楚。我们的研究旨在评估 COX-2 在 HPS 患者血清刺激下对 HPMVEC 定向集体迁移的潜在影响。在这项研究中，筛选了 9 例稳定的肝硬化患者是否存在 HPS。我们证实，HPS 患者血清显著促进了 HPMVEC 的定向集体迁移和血管生成，而 COX-2 选择性拮抗剂帕瑞昔布钠可显著抑制 HPS 患者血清刺激下 HPMVEC 的定向集体迁移。此外，HPS 患者血清显著上调 PKC 的磷酸化，并通过 COX-2/PGE2 信号通路促进 Rac 的激活。值得注意的是，沉默 PKC 激活可减弱 HPS 患者血清诱导的 HPMVEC 定向集体迁移。总之，这些结果表明 COX-2 诱导的 PKC/Rac 信号通路调节了 HPS 患者病理性肺血管生成过程中 HPMVEC 的定向集体迁移。
