title: Defective retinal vascular endothelial cell development as a consequence of impaired integrin αVβ8-mediated activation of transforming growth factor-β.
abstract: Deletions of the genes encoding the integrin αVβ8 (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 TGFβ 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 Müller glia and neurons, but not deletion in astrocytes, recapitulates the phenotype observed following Itgb8 in the entire retina. Consistent with αVβ8's role in TGFβ1 activation, we show that retinal deletion of Tgfb1 results in very similar retinal vascular abnormalities. The vascular deficits appear to reflect impaired TGFβ signaling in vascular endothelial cells because retinal deletion of Itgb8 reduces phospho-SMAD3 in endothelial cells and endothelial cell-specific deletion of the TGFβRII gene recapitulates the major deficits observed in the Itgb8 and TGFβ1 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 TGFβ activation and signaling.
authors.affiliation: Department of Pediatrics, VA Medical Center, University of California, San Francisco, San Francisco, California 95158, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Arnold
authors.forename: Gina M
authors.initials: GM
authors.lastname: Ferrero
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qiu
authors.forename: Isabella T
authors.initials: IT
authors.lastname: Phan
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Akhurst
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D042783:Endothelial Cells / Q000473:pathology* / Q000502:physiology; D005260:Female; D016023:Integrins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012171:Retinal Vessels / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016023:Integrins; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C403414:integrin alphavbeta8