title: Vessel maturation schedule determines vulnerability to neuronal injuries of prematurity.
abstract: Premature birth is a major risk factor for multiple brain pathologies, notably periventricular leukomalacia (PVL), which is distinguished by bilateral necrosis of neural tissue around the ventricles and a sequela of neurological disturbances. The 2 hallmarks of brain pathologies of prematurity are a restricted gestational window of vulnerability and confinement of injury to a specific cerebral region. Here, we examined the proposition that both of these features are determined by the state of blood vessel immaturity. We developed a murine genetic model that allows for inducible and reversible VEGF blockade during brain development. Using this system, we determined that cerebral vessels mature in a centrifugal, wave-like fashion that results in sequential acquisition of a functional blood-brain barrier and exit from a VEGF-dependent phase, with periventricular vessels being the last to mature. This developmental program permitted selective ablation of periventricular vessels via episodic VEGF blockade within a specific, vulnerable gestational window. Enforced collapse of ganglionic eminence vessels and resultant periventricular neural apoptosis resulted in a PVL-like phenotype that recapitulates the primary periventricular lesion, ventricular enlargement, and the secondary cortical deficit in out-migrating GABAergic inhibitory interneurons. These findings provide an animal model that reproduces the temporal and spatial specificities of PVL and indicate that damage to VEGF-dependent, immature periventricular vessels contributes to PVL development.
authors.forename: Tamar
authors.initials: T
authors.lastname: Licht
authors.forename: Talia
authors.initials: T
authors.lastname: Dor-Wollman
authors.forename: Ayal
authors.initials: A
authors.lastname: Ben-Zvi
authors.forename: Gadiel
authors.initials: G
authors.lastname: Rothe
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier; D015687:Cell Hypoxia; D002552:Cerebral Ventricles / Q000098:blood supply / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007395:Interneurons / Q000502:physiology; D007969:Leukomalacia, Periventricular / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D009474:Neurons / Q000502:physiology; D011247:Pregnancy; D047928:Premature Birth / Q000503:physiopathology; D014158:Transcription, Genetic; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D040281:Vascular Endothelial Growth Factor Receptor-1