Trouillet Alix, Lorach Henri, Dubus Elisabeth, El Mathari Brahim, Ivkovic Ivana, Dégardin Julie, Simonutti Manuel, Paques Michel, Guillonneau Xavier, Sennlaub Florian, Sahel José-Alain, Ronco Pierre, Plaisier Emmanuelle, Picaud Serge
INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
Fovea Sanofi, Paris, France.
Neurobiol Dis. 2017 Apr;100:52-61. doi: 10.1016/j.nbd.2016.12.014. Epub 2017 Jan 3.
The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling.
This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition.
HANAC综合征由编码胶原蛋白4a1（血管基底膜的主要成分）的基因突变引起。眼部症状包括血管迂曲增加和偶尔的出血。为了研究血管缺陷如何影响神经元功能，我们分析了HANAC小鼠模型的视网膜表型。杂合突变小鼠在视网膜血管和布鲁赫膜中均表现出基底膜变薄，导致血管渗漏。纯合小鼠有额外的血管变化，包括更大的血管覆盖范围和迂曲度。这种更大的迂曲度与血管内皮生长因子（VEGF）的较高表达水平相关。血管的这些主要变化与光感受器功能障碍和变性相关。神经元损伤与星形胶质细胞和米勒胶质细胞中的反应性胶质增生以及小胶质细胞迁移到外视网膜有关。这项研究说明了在一个新的HANAC综合征模型中血管变化如何引发神经元变性，该模型可用于进一步研究神经血管耦合功能障碍。
本研究提供了一种针对HANAC综合征新型小鼠模型的视网膜方面的表型分析。它概括了人类疾病的大多数方面，因此是研究和解决这种疾病的一个很好的工具。
