Nitric oxide and endothelin secretion by brain microvessel endothelial cells: Regulation by cyclic nucleotides

Abstract

Endothelin (ET)-1 was originally characterized as a potent vasoconstrictor peptide secreted by vascular endothelial cells. It possesses a wide range of biological activities within the cardiovascular system and in other organs, including the brain. Also secreted by endothelial cells, nitric oxide (NO), has recently been identified as a relaxing factor, as well as a pleiotropic mediator, second messenger, immune defence molecule, and neurotransmitter. Most of the data concerning the secretion of these two agents in vitro has been collected from studies on macrovascular endothelial cells. Given the remarkable heterogeneity of endothelia in terms of morphology and function, we have analyzed the ability of brain microvessel endothelial cells in vitro to release ET-1 and NO, which, at the level of the blood-brain barrier, have perivascular astrocytes as potential targets. The present study was performed with immortalized rat brain microvessel endothelial cells, which display in culture a non transformed phenotype. Our data demonstrate that: (1) these cells release NO when induced by IFN gamma and TNF alpha, (2) they constitutively secrete ET-1, and (3) cAMP potentiates the cytokine-induced NO release and exerts a biphasic regulation on ET-1 secretion: micromolar concentrations of 8-Br-cAMP inhibit and higher doses stimulate ET-1 secretion. This stimulation is blocked by EGTA and the calmodulin antagonist W7, but not by protein kinase C inhibitors, suggesting the involvement of the calmodulin branch of the calcium messenger system. These results suggest that cerebral microvessel endothelial cells may participate in vivo to the regulation of glial activity in the brain through the release of NO and ET-1.

Endothelial cell implantation and survival within experimental gliomas.

“…The immortalized microvascular endothelial cell line from rat brain (33) modified to express the nls-lacZ reporter gene (RBEZ) (22) was used to explore endothelial implantation to 9L, F98, and C6 rat gliomas in vivo. In these studies, glioma cells alone or a mixture of RBEZ cells and glioma cells were implanted to rat caudate/putamen.…”

ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells

“…In addition, EC also regulate the passage of nutrients and cellular trafficking between the blood and underlining tissue [i.e., blood-brain barrier (BBB) permeability] (28). Among a number of vasoactive factors that play pivotal roles in regulating vascular reactivity are endothelin (ET)-1 and nitric oxide (NO), which are produced locally in adjunct cells or found in the circulation (1,9,22,24,32).…”

Stimulation of phospholipase C in cultured microvascular endothelial cells from human frontal lobe by histamine, endothelin and purinoceptor agonists

“…An ETB receptor sensitive to ET-3, but not PLC-linked, has been described in bovine brain endothelial cells (Vigne et al, 1991). The origin of ET-1 acting on the ETA receptors described here is unclear, although ET-1 mRNA has been described in extracts of rat cerebellar astroglial cells (MacCumber et al, 1990) and has recently been reported to be secreted by an immortalised rat brain microvessel endothelial cell line (Durieu-Trautmann et al, 1993).…”