Chemical induction of fenestrae in vessels of the blood-brain barrier.

The endothelium responsible for the blood-brain barrier to hydrophilic solutes has been converted here, by chemical means, to the fenestrated, permeable type of vessel (FV). During development, some brain vessels are reported to be transiently fenestrated. Endothelial fenestrae of adrenal glands are known to be reinduced in vitro by retinoic acid (RA) or phorbol myristate acetate (PMA). Could fenestrae be likewise reinduced in brain barrier vessels? When RA or PMA were infused continuously by an osmotic pump for 28 days into the cerebral cortex of rats, some brain vessels in the lesion cavity created by the reagents were FV. There were no FV in adjacent brain. When 100 microM RA was infused, about 20% of vessels in the cyst were FV, as were about 29% after infusion of 150 ng/ml PMA. Fenestra development depended on concentration and time. Reversibility of fenestra formation was complete at 1-2 months after delivery of RA or PMA had ceased. It is proposed that the RA and PMA effect is mediated by the plasminogen activator urokinase, in as much as both RA and PMA stimulate its production. This notion is supported by preliminary experiments in which urokinase infusion into brain also produced fenestrae. It is further suggested that the reversible induction of fenestrae in the mature brain by RA, PMA, and, perhaps, a variety of other conversion factors may be confined to a subset of brain barrier vessels that must be regenerating and of the kind that were temporarily fenestrated during fetal life.