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

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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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Acknowledgments

This study was supported by grants to HS from the National Institutes of Health (R01 NS027713, R01 HL122774 and R21 NS083788), and from the Michael Ryan Zodda Foundation and the UCSF Research Evaluation and Allocation Committee (REAC). We thank members of the UCSF BAVM Study Project (http://avm.ucsf.edu) for their support, and Voltaire Gungab for his assistance with manuscript preparation.

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Correspondence to Hua Su.

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Funding

This study was supported by grants to Hua Su from the National Institutes of Health (R01 NS027713, R01 HL122774 and R21 NS083788), and from the Michael Ryan Zodda Foundation and the UCSF Research Evaluation and Allocation Committee (REAC).

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were approved by and were in accordance with the ethical standards of the Institutional Animal Care and Use Committee of the University of California San Francisco.

Additional information

Li Ma and Fanxia Shen contributed equally to this work.

Dr. Young passed away 3 years ago.

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Ma, L., Shen, F., Jun, K. et al. Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice. Transl. Stroke Res. 7, 488–496 (2016). https://doi.org/10.1007/s12975-016-0478-2

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