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Lack of Flvcr2 impa...
Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier
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- Santander, Nicolas (author)
- UCSF, Dept Pediat, San Francisco, CA USA.
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- Lizama, Carlos O. (author)
- UCSF, Cardiovasc Res Inst, San Francisco, CA USA.
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- Meky, Eman (author)
- UCSF, Dept Pediat, San Francisco, CA USA.
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- McKinsey, Gabriel L. (author)
- UCSF, Dept Pediat, San Francisco, CA USA.
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- Jung, Bongnam (author)
- Karolinska Inst, Integrated Cardiometab Ctr, Dept Med, Solna, Sweden.
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- Sheppard, Dean (author)
- UCSF, Dept Cell Biol, San Francisco, CA USA.
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- Betsholtz, Christer (author)
- Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Integrated Cardiometab Ctr, Dept Med, Solna, Sweden.
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- Arnold, Thomas D. (author)
- UCSF, Dept Pediat, San Francisco, CA USA.
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UCSF, Dept Pediat, San Francisco, CA USA UCSF, Cardiovasc Res Inst, San Francisco, CA USA. (creator_code:org_t)
- 2020
- 2020
- English.
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In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:8, s. 4055-4068
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Subject headings
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- 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 showed that Flvcr2 was necessary for angiogenic sprouting in the brain, but surprisingly dispensable for maintaining the blood-brain barrier. Endothelial cells lacking Flvcr2 had altered expression of angiogenic factors, failed to adopt tip cell properties, and displayed reduced sprouting, leading to vascular malformations similar to those seen in humans with Fowler syndrome. Brain hypovascularization was 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 was maintained in Flvcr2 mutant mice. Our Fowler syndrome model therefore defined the pathobiology of this disease and provided new insights into brain angiogenesis by showing uncoupling of vessel morphogenesis and blood-brain barrier formation.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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