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Translational Stroke Research

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29.06.2016 | Original Article

Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice

verfasst von: Li Ma, Fanxia Shen, Kristine Jun, Chen Bao, Robert Kuo, William L. Young, Stephen L. Nishimura, Hua Su

Erschienen in: Translational Stroke Research | Ausgabe 6/2016

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Abstract

Brain arteriovenous malformation (bAVM), characterized by tangled dysplastic vessels, is an important cause of intracranial hemorrhage in young adults, and its pathogenesis and progression are not fully understood. Patients with haploinsufficiency of transforming growth factor-β (TGF-β) receptors, activin receptor-like kinase 1 (ALK1) or endoglin (ENG) have a higher incidence of bAVM than the general population. However, bAVM does not develop effectively in mice with the same haploinsufficiency. The expression of integrin β8 subunit (ITGB8), another member in the TGF-β superfamily, is reduced in sporadic human bAVM. Brain angiogenic stimulation results at the capillary level of vascular malformation in adult Alk1 haploinsufficient (Alk1 ^+/−) mice. We hypothesized that deletion of Itgb8 enhances bAVM development in adult Alk1 ^+/− mice. An adenoviral vector expressing Cre recombinase (Ad-Cre) was co-injected with an adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) into the brain of Alk1 ^+/−;Itgb8-floxed mice to induce focal Itgb8 gene deletion and angiogenesis. We showed that compared with Alk ^+/− mice (4.75 ± 1.38/mm²), the Alk1 ^+/−;Itgb8-deficient mice had more dysplastic vessels in the angiogenic foci (7.14 ± 0.68/mm², P = 0.003). More severe hemorrhage was associated with dysplastic vessels in the brain of Itgb8-deleted Alk1 ^+/−, as evidenced by larger Prussian blue-positive areas (1278 ± 373 pixels/mm² vs. Alk1 ^+/− : 320 ± 104 pixels/mm²; P = 0.028). These data indicate that both Itgb8 and Alk1 are important in maintaining normal cerebral angiogenesis in response to VEGF. Itgb8 deficiency enhances the formation of dysplastic vessels and hemorrhage in Alk1 ^+/− mice.

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Titel: Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice
verfasst von: Li Ma
Fanxia Shen
Kristine Jun
Chen Bao
Robert Kuo
William L. Young
Stephen L. Nishimura
Hua Su
Publikationsdatum: 29.06.2016
Verlag: Springer US
Erschienen in: Translational Stroke Research / Ausgabe 6/2016
Print ISSN: 1868-4483
Elektronische ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-016-0478-2

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Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice

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