Keuters Meike Hedwig, Antila Salli, Immonen Riikka, Plotnikova Lidiia, Wojciechowski Sara, Lehtonen Sarka, Alitalo Kari, Koistinaho Jari, Dhungana Hiramani
Neuroscience Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, 00014, Helsinki, Finland.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210, Kuopio, Finland.
Transl Stroke Res. 2025 Jun;16(3):781-799. doi: 10.1007/s12975-024-01262-9. Epub 2024 Jun 1.
Timely relief of edema and clearance of waste products, as well as promotion of anti-inflammatory immune responses, reduce ischemic stroke pathology, and attenuate harmful long-term effects post-stroke. The discovery of an extensive and functional lymphatic vessel system in the outermost meningeal layer, dura mater, has opened up new possibilities to facilitate post-stroke recovery by inducing dural lymphatic vessel (dLV) growth via a single injection of a vector encoding vascular endothelial growth factor C (VEGF-C). In the present study, we aimed to improve post-stroke outcomes by inducing dLV growth in mice. We injected mice with a single intracerebroventricular dose of adeno-associated viral particles encoding VEGF-C before subjecting them to transient middle cerebral artery occlusion (tMCAo). Behavioral testing, Gadolinium (Gd) contrast agent-enhanced magnetic resonance imaging (MRI), and immunohistochemical analysis were performed to define the impact of VEGF-C on the post-stroke outcome. VEGF-C improved stroke-induced behavioral deficits, such as gait disturbances and neurological deficits, ameliorated post-stroke inflammation, and enhanced an alternative glial immune response. Importantly, VEGF-C treatment increased the drainage of brain interstitial fluid (ISF) and cerebrospinal fluid (CSF), as shown by Gd-enhanced MRI. These outcomes were closely associated with an increase in the growth of dLVs around the region where we observed increased vefgc mRNA expression within the brain, including the olfactory bulb, cortex, and cerebellum. Strikingly, VEGF-C-treated ischemic mice exhibited a faster and stronger Gd-signal accumulation in ischemic core area and an enhanced fluid outflow via the cribriform plate. In conclusion, the VEGF-C-induced dLV growth improved the overall outcome post-stroke, indicating that VEGF-C has potential to be included in the treatment strategies of post-ischemic stroke. However, to maximize the therapeutic potential of VEGF-C treatment, further studies on the impact of an enhanced dural lymphatic system at clinically relevant time points are essential.
及时消除水肿和清除代谢废物，以及促进抗炎免疫反应，可减轻缺血性中风的病理变化，并减轻中风后的有害长期影响。在最外层脑膜即硬脑膜中发现广泛且具有功能的淋巴管系统，为通过单次注射编码血管内皮生长因子C（VEGF-C）的载体诱导硬脑膜淋巴管（dLV）生长来促进中风后恢复开辟了新的可能性。在本研究中，我们旨在通过诱导小鼠dLV生长来改善中风后的结果。在对小鼠进行短暂性大脑中动脉闭塞（tMCAo）之前，向其脑室内单次注射编码VEGF-C的腺相关病毒颗粒。进行行为测试、钆（Gd）造影剂增强磁共振成像（MRI）和免疫组织化学分析，以确定VEGF-C对中风后结果的影响。VEGF-C改善了中风引起的行为缺陷，如步态障碍和神经功能缺损，减轻了中风后的炎症，并增强了替代性胶质免疫反应。重要的是，如Gd增强MRI所示，VEGF-C治疗增加了脑间质液（ISF）和脑脊液（CSF）的引流。这些结果与我们观察到大脑内VegfC mRNA表达增加区域（包括嗅球、皮质和小脑）周围dLV生长的增加密切相关。令人惊讶的是，VEGF-C治疗的缺血小鼠在缺血核心区域表现出更快、更强的Gd信号积累，以及通过筛板增强的液体流出。总之，VEGF-C诱导的dLV生长改善了中风后的总体结果，表明VEGF-C有潜力纳入缺血性中风的治疗策略。然而，为了最大限度地发挥VEGF-C治疗的潜力，在临床相关时间点对增强的硬脑膜淋巴系统的影响进行进一步研究至关重要。
