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1.
Nat Cardiovasc Res ; 3: 474-491, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-39087029

RESUMO

Discovery of meningeal lymphatic vessels (LVs) in the dura mater, also known as dural LVs (dLVs) that depend on vascular endothelial growth factor C expression, has raised interest in their possible involvement in Alzheimer's disease (AD). Here we find that in the APdE9 and 5xFAD mouse models of AD, dural amyloid-ß (Aß) is confined to blood vessels and dLV morphology or function is not altered. The induction of sustained dLV atrophy or hyperplasia in the AD mice by blocking or overexpressing vascular endothelial growth factor C, impaired or improved, respectively, macromolecular cerebrospinal fluid (CSF) drainage to cervical lymph nodes. Yet, sustained manipulation of dLVs did not significantly alter the overall brain Aß plaque load. Moreover, dLV atrophy did not alter the behavioral phenotypes of the AD mice, but it improved CSF-to-blood drainage. Our results indicate that sustained dLV manipulation does not affect Aß deposition in the brain and that compensatory mechanisms promote CSF clearance.

2.
Transl Stroke Res ; 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822994

RESUMO

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.

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