Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Am J Pathol. 2019 Apr;189(4):762-772. doi: 10.1016/j.ajpath.2019.01.008. Epub 2019 Jan 31.
Increased angiogenesis is a characteristic feature of remodeling in asthmatic airways and stems from the imbalance between pro-angiogenic and anti-angiogenic factors. Surprisingly, the factors regulating this process in allergic asthma are poorly defined. Previously, we showed an important role of semaphorins 3E (Sema3E) in growth factor-induced airway smooth muscle proliferation and migration in vitro, and in down-regulating airway inflammation, T helper 2/T helper 17 cytokine response, mucus cell hyperplasia, and airway hyperresponsiveness in vivo. However, the role of Sema3E in airway angiogenesis is not fully understood. Here, we investigated the role of Sema3E in airway angiogenesis using a house dust mite (HDM) murine model of allergic asthma. Intranasal treatment with recombinant Sema3E significantly reduced the expression of angiogenesis markers within the airways of HDM-challenged mice compared with untreated mice. HDM-induced expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 protein were diminished substantially on Sema3E treatment. Interestingly, Sema3E-treated mice showed an enhanced expression of the negative regulator of angiogenesis, soluble VEGF receptor 1, compared with the untreated mice. These events were reversed in Sema3E-deficient mice at baseline or on HDM challenge. Taken together, this study provides the first evidence that Sema3E modulates angiogenesis in allergic asthmatic airways via modulating pro- and anti-angiogenic factors.
血管生成增加是哮喘气道重塑的特征，源于促血管生成和抗血管生成因子之间的失衡。令人惊讶的是，调节变应性哮喘中这一过程的因素还没有完全确定。之前，我们已经表明，信号素 3E（Sema3E）在体外生长因子诱导的气道平滑肌增殖和迁移以及下调气道炎症、辅助性 T 细胞 2/辅助性 T 细胞 17 细胞因子反应、黏液细胞增生和气道高反应性方面具有重要作用。然而，Sema3E 在气道血管生成中的作用尚未完全阐明。在这里，我们使用屋尘螨（HDM）诱导的变应性哮喘小鼠模型研究了 Sema3E 在气道血管生成中的作用。与未治疗的小鼠相比，重组 Sema3E 鼻内给药可显著降低 HDM 挑战小鼠气道中血管生成标志物的表达。Sema3E 处理可显著降低 HDM 诱导的血管内皮生长因子（VEGF）和 VEGF 受体 2 蛋白的表达。有趣的是，与未治疗的小鼠相比，Sema3E 处理的小鼠表现出抗血管生成因子可溶性 VEGF 受体 1 的表达增强。在 Sema3E 缺陷小鼠中，这些事件在基线或 HDM 挑战时都被逆转。总之，这项研究首次表明 Sema3E 通过调节促血管生成和抗血管生成因子来调节变应性哮喘气道中的血管生成。
