Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier.
Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier.
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DOI：
10.1172/jci136578
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发表时间：
2020-05
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通讯作者：
Nicolás Santander;C. Lizama;Eman M. Meky;Gabriel Mckinsey;Bongnam Jung;D. Sheppard;C. Betsholtz;Thomas D. Arnold
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作者：
Nicolás Santander;C. Lizama;Eman M. Meky;Gabriel Mckinsey;Bongnam Jung;D. Sheppard;C. Betsholtz;Thomas D. Arnold
福勒综合征是一种罕见的常染色体隐性遗传性脑血管疾病，由人类 FLVCR2 突变引起。该疾病发生在脑血管发育的关键时期，其特征是肾小球样血管病变和脑积水，并且几乎总是在产前致命。在这里，我们试图通过灭活小鼠中的 Flvcr2 来深入了解脑血管形成的过程和福勒综合征的发病机制。我们发现 Flvcr2 对于大脑中的血管生成是必需的，但令人惊讶的是对于维持血脑屏障来说却是可有可无的。缺乏 Flvcr2 的内皮细胞会改变血管生成因子的表达，无法采用尖端细胞特性，并显示出芽减少，导致血管畸形，类似于福勒综合征患者的血管畸形。脑血管形成不足与缺氧和组织梗塞有关，最终导致突变动物脑积水和死亡。引人注目的是，尽管 Flvcr2 突变小鼠存在严重的血管异常和脑组织梗塞，但血脑屏障仍得以维持。因此，我们的新福勒综合征模型定义了这种疾病的病理学，并通过显示血管形态发生和血脑屏障形成的解偶联为脑血管生成提供了新的见解。
Fowler syndrome is a rare autosomal recessive brain vascular disorder caused by mutation in FLVCR2 in humans. The disease occurs during a critical period of brain vascular development, is characterized by glomeruloid vasculopathy and hydrocephalus, and is almost invariably prenatally fatal. Here, we sought to gain insights into the process of brain vascularization and the pathogenesis of Fowler Syndrome by inactivating Flvcr2 in mice. We show that Flvcr2 is necessary for angiogenic sprouting in the brain, but surprisingly dispensable for maintaining the blood brain barrier. Endothelial cells lacking Flvcr2 have altered expression of angiogenic factors, fail to adopt tip-cell properties and display reduced sprouting leading to vascular malformations similar to those seen in humans with Fowler Syndrome. Brain hypo-vascularization is associated with hypoxia and tissue infarction, ultimately causing hydrocephalus and death of mutant animals. Strikingly, despite severe vascular anomalies and brain tissue infarction, the blood-brain barrier is maintained in Flvcr2 mutant mice. Our new Fowler syndrome models therefore define the pathobiology of this disease, and provide new insights into brain angiogenesis by showing uncoupling of vessel morphogenesis and blood-brain barrier formation.