We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Defective Retinal Vascular Endothelial Cell Development As a Consequence of Impaired Integrin &agr;V&bgr;8-Mediated Activation of Transforming Growth Factor-&bgr;.
- Authors
Arnold, Thomas D.; Ferrero, Gina M.; Haiyan Qiu; Phan, Isabella T.; Akhurst, Rosemary J.; Huang, Eric J.; Reichardt, Louis F.
- Abstract
Deletions of the genes encoding the integrin &agr;V&bgr;8 (Itgav, Itgb8) have been shown to result in abnormal vascular development in the CNS, including prenatal and perinatal hemorrhage. Other work has indicated that a major function of this integrin in vivo is to promote TGF&bgr; activation. In this paper, we show that Itgb8 mRNA is strongly expressed in murine Müller glia and retinal ganglion cells, but not astrocytes. We further show that Itgb8 deletion in the entire retina severely perturbs development of the murine retinal vasculature, elevating vascular branch point density and vascular coverage in the superficial vascular plexus, while severely impairing formation of the deep vascular plexus. The stability of the mutant vasculature is also impaired as assessed by the presence of hemorrhage and vascular basal lamina sleeves lacking endothelial cells. Specific deletion of Itgb8 in Muuml;ller glia and neurons, but not deletion in astrocytes, recapitulates the phenotype observed following Itgb8 in the entire retina. Consistent with&agr;V&bgr;8's role in TGF&bgr;1 activation, we show that retinal deletion of Tgfb1 results in very similar retinal vascular abnormalities. The vascular deficits appear to reflect impaired TGF&bgr; signaling in vascular endothelial cells because retinal deletion of Itgb8 reduces phospho-SMAD3 in endothelial cells and endothelial cell-specific deletion of the TGF&bgr;RII gene recapitulates the major deficits observed in the Itgb8 and TGF&bgr;1 mutants. Of special interest, the retinal vascular phenotypes observed in each mutant are remarkably similar to those of others following inhibition of neuropilin-1, a receptor previously implicated in TGF&bgr; activation and signaling.
- Subjects
VASCULAR endothelium; RETINAL blood vessels; INTEGRINS; TRANSFORMING growth factors-beta; GENETIC code; CENTRAL nervous system abnormalities; HEMORRHAGE
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 4, p1197
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5648-11.2012