title: Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain.
abstract: 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, Pdgfb(ret/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.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-177 77 Stockholm, Sweden arnoldtd@gmail.com LReichardt@simonsfoundation.org.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Arnold
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-177 77 Stockholm, Sweden.
authors.forename: Colin
authors.initials: C
authors.lastname: Niaudet
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-177 77 Stockholm, Sweden.
authors.forename: Mei-Fong
authors.initials: MF
authors.lastname: Pang
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Siegenthaler
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-177 77 Stockholm, Sweden.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Gaengel
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-177 77 Stockholm, Sweden.
authors.forename: Bongnam
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of Physiology and Neuroscience Program, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Ferrero
authors.affiliation: Laboratory of Stem Cell and Neuro-Vascular Biology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Yoh-suke
authors.initials: YS
authors.lastname: Mukouyama
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-177 77 Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Fuxe
authors.affiliation: Helen Diller Cancer Center and Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Akhurst
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-177 77 Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.affiliation: Department of Physiology and Neuroscience Program, University of California, San Francisco, San Francisco, CA 94158, USA arnoldtd@gmail.com LReichardt@simonsfoundation.org.
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D002452:Cell Count; D002543:Cerebral Hemorrhage / Q000209:etiology*; D042783:Endothelial Cells / Q000502:physiology; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000150:complications*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016023:Integrins; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8
keywords: Angiogenesis; Brain; CNS; Hemorrhage; Integrin αVβ8; Mouse; Sprouting; TGFβ