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Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain
- Source :
- Arnold, TD; Niaudet, C; Pang, MF; Siegenthaler, J; Gaengel, K; Jung, B; et al.(2014). Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain. Development (Cambridge), 141(23), 4489-4499. doi: 10.1242/dev.107193. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/0k9975z5, Development (Cambridge, England), vol 141, iss 23
- Publication Year :
- 2014
- Publisher :
- eScholarship, University of California, 2014.
-
Abstract
- © 2014. Published by The Company of Biologists Ltd. Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfbret/ret mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.
- Subjects :
- Integrins
Mouse
1.1 Normal biological development and functioning
Cell Count
Hemorrhage
Cardiovascular
Medical and Health Sciences
Mice
TGFβ
Integrin αVβ8
Underpinning research
Transforming Growth Factor beta
TGF beta
Animals
2.1 Biological and endogenous factors
Aetiology
Neovascularization
Cerebral Hemorrhage
Pathologic
Microscopy
Analysis of Variance
Neurosciences
Brain
Endothelial Cells
Biological Sciences
Stem Cell Research
Immunohistochemistry
Brain Disorders
Stroke
Blood-Brain Barrier
Confocal
Integrin alpha V beta 8
cardiovascular system
Stem Cell Research - Nonembryonic - Non-Human
Angiogenesis
CNS
Sprouting
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Arnold, TD; Niaudet, C; Pang, MF; Siegenthaler, J; Gaengel, K; Jung, B; et al.(2014). Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain. Development (Cambridge), 141(23), 4489-4499. doi: 10.1242/dev.107193. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/0k9975z5, Development (Cambridge, England), vol 141, iss 23
- Accession number :
- edsair.dedup.wf.001..48e174c996b9f7eba718207889de3aec