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 fenestrate d, permeable type of vessel (FV). During development, some brain vesse ls are reported to be transiently fenestrated. Endothelial fenestrae o f adrenal glands are known to be reinduced in vitro by retinoic acid ( RA) or phorbol myristate acetate (PMA). Could fenestrae be likewise re induced in brain barrier vessels? When RA or PMA were infused continuo usly 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 F V,There were no FV in adjacent brain, When 100 mu M RA was infused, ab out 20% of vessels in the cyst were FV, as were about 29% after infusi on of 150 ng/ml PMA. Fenestra development depended on concentration an d 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 an d PMA effect is mediated by the plasminogen activator urokinase, in as much as both RA and PMA stimulate its production, This notion is supp orted by preliminary experiments in which urokinase infusion into brai n 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 b rain barrier vessels that must be regenerating and of the kind that we re temporarily fenestrated during fetal life. (C) 1996 Academic Press, Inc.