Zika virus impairs the development of blood vessels in a mouse model of congenital infection

Garcez, P P and Stolp, H B and Sravanam, S and Christoff, R R and Ferreira, J C C G and Dias, A A and Pezzuto, P and Higa, L M and Barbeito-Andrés, J and Ferreira, R O and Andrade, C B V and Siqueira, M and Santos, T M P and Drumond, J and Hoerder-Suabedissen, A and De Lima, C V F and Tovar-Moll, F and Lopes, R T and Fragel-Madeira, L and Lent, R and Ortiga-Carvalho, T M and Stipursky, J and Bellio, M and Tanuri, A and Molnár, Z (2018) Zika virus impairs the development of blood vessels in a mouse model of congenital infection. Scientific Reports (Nature), 8. p. 12774.

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Zika virus (ZIKV) is associated with brain development abnormalities such as primary microcephaly, a severe reduction in brain growth. Here we demonstrated in vivo the impact of congenital ZIKV infection in blood vessel development, a crucial step in organogenesis. ZIKV was injected intravenously in the pregnant type 2 interferon (IFN)-deficient mouse at embryonic day (E) 12.5. The embryos were collected at E15.5 and postnatal day (P)2. Immunohistochemistry for cortical progenitors and neuronal markers at E15.5 showed the reduction of both populations as a result of ZIKV infection. Using confocal 3D imaging, we found that ZIKV infected brain sections displayed a reduction in the vasculature density and vessel branching compared to mocks at E15.5; altogether, cortical vessels presented a comparatively immature pattern in the infected tissue. These impaired vascular patterns were also apparent in the placenta and retina. Moreover, proteomic analysis has shown that angiogenesis proteins are deregulated in the infected brains compared to controls. At P2, the cortical size and brain weight were reduced in comparison to mock-infected animals. In sum, our results indicate that ZIKV impairs angiogenesis in addition to neurogenesis during development. The vasculature defects represent a limitation for general brain growth but also could regulate neurogenesis directly.

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