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Vessel maturation schedule determines vulnerability to neuronal injuries of prematurity
Tamar Licht, … , Gadiel Rothe, Eli Keshet
Tamar Licht, … , Gadiel Rothe, Eli Keshet
Published February 17, 2015
Citation Information: J Clin Invest. 2015;125(3):1319-1328. https://doi.org/10.1172/JCI79401.
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Research Article

Vessel maturation schedule determines vulnerability to neuronal injuries of prematurity

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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

Tamar Licht, Talia Dor-Wollman, Ayal Ben-Zvi, Gadiel Rothe, Eli Keshet

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Figure 1

A system for brain-specific, conditional VEGF LOF.

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A system for brain-specific, conditional VEGF LOF.
(A) A schematic of th...
(A) A schematic of the “driving” CamkIIα-tTA transgene and the “responder” tetracycline-regulated sVEGFR1 transgene composing the conditionally induced bitransgenic system. (B) Immunostaining of sagittal E16.5 embryo sections for human VEGFR1 (not detecting endogenous receptor variants) in the presence (“off” mode) or absence (“on” mode) of tetracycline. (C) Immunostaining of adult (6 months old) brain sections for hVEGFR1 maintained in the off mode (left), on mode (middle), or an on/off mode (right). Note full reversibility of transgene induction. Images were reproduced 6 times. Scale bars: 100 μm. V, lateral ventricle; CP, choroid plexus.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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