Oregon Hearing Research Center, Department of Otolaryngology / Head & Neck Surgery, Oregon Health & Science University, Portland, OR, 97239, USA; Boston Children's Hospital, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
Oregon Hearing Research Center, Department of Otolaryngology / Head & Neck Surgery, Oregon Health & Science University, Portland, OR, 97239, USA.
Hear Res. 2019 Jun;377:179-188. doi: 10.1016/j.heares.2019.03.010. Epub 2019 Mar 29.
Can damaged or degenerated vessels be regenerated in the ear? The question is clinically important, as disruption of cochlear blood flow is seen in a wide variety of hearing disorders, including in loud sound-induced hearing loss (endothelial injury), ageing-related hearing loss (lost vascular density), and genetic hearing loss (e.g., Norrie disease: strial avascularization). Progression in cochlear blood flow (CBF) pathology can parallel progression in hair cell and hearing loss. However, neither new vessel growth in the ear, nor the role of angiogenesis in hearing, have been investigated. In this study, we used an established ex vivo tissue explant model in conjunction with a matrigel matrix model to demonstrate for the first time that new vessels can be generated by activating a vascular endothelial growth factor (VEGF-A) signal. Most intriguingly, we found that the pattern of the newly formed vessels resembles the natural 'mesh pattern' of in situ strial vessels, with both lumen and expression of tight junctions. Sphigosine-1-phosphate (S1P) in synergy with VEGF-A control new vessel size and growth. Using transgenic neural/glial antigen 2 (NG2) fluorescent reporter mice, we have furthermore discovered that the progenitors of "de novo" strial vessels are NG2-derived cells. Taken together, our data demonstrates that damaged strial microvessels can be regenerated by reprogramming NG2-derived angiogenic cells. Restoration of the functional vasculature may be critical for recovery of vascular dysfunction related hearing loss.
受损或退化的血管能在耳朵中再生吗？这个问题在临床上很重要，因为耳蜗血流的中断可见于各种听力障碍，包括强声诱导的听力损失（内皮损伤）、与年龄相关的听力损失（血管密度丧失）和遗传性听力损失（如 Norrie 病：嵴血管化缺失）。耳蜗血流（CBF）病理的进展可以与毛细胞和听力损失的进展平行。然而，尚未研究内耳中的新血管生长或血管生成在听力中的作用。在这项研究中，我们使用了一种已建立的离体组织外植体模型，并结合基质胶基质模型，首次证明可以通过激活血管内皮生长因子（VEGF-A）信号来产生新血管。最有趣的是，我们发现新形成的血管的模式类似于原位嵴血管的天然“网状模式”，具有管腔和紧密连接的表达。鞘氨醇-1-磷酸（S1P）与 VEGF-A 协同控制新血管的大小和生长。使用转基因神经/神经胶质抗原 2（NG2）荧光报告小鼠，我们还发现“新”嵴血管的祖先是 NG2 衍生的细胞。总之，我们的数据表明，受损的嵴微血管可以通过重编程 NG2 衍生的血管生成细胞来再生。功能性血管的恢复对于恢复与血管功能障碍相关的听力损失可能至关重要。
