UP-REGULATION OF COX-2 IN CEREBRAL MICROVASCULAR ENDOTHELIAL-CELLS BYSMOOTH-MUSCLE CELL SIGNALS

Cyclooxygenase (COX) isoform expression, intracellular localization, a nd function in endothelial cells from the newborn pig cerebral microve ssels were investigated using COX-1- and COX-2-specific antibodies and the COX-2 inhibitor NS-398. Cerebral microvessels, microvascular endo thelium, and cultured endothelial cells constitutively express both CO X-1 and COX-2. NS-398 inhibits 70-90% of endothelial prostanoid produc tion. Endothelial cells grown in noncontact coculture with smooth musc le cells for 24-48 h demonstrate a stable induction of COX-2 protein a nd an NS-398-sensitive increase in prostanoid synthesis. The induction of endothelial COX in mixed cell coculture is accompanied by intracel lular redistribution of COX-2. In cocultured endothelial cells, COX-2 is observed in the nucleus, nuclear envelope, and cytoplasm, compared with the mainly intranuclear localization of COX-2 in cells cultured s eparately. No changes were observed in COX-1 protein, localized in end othelial cell cytoplasm and the nuclear envelope. These results indica te that smooth muscle cells may modify endothelial function by upregul ating COX-2, which is a major functional COX isoform in cerebral micro vascular endothelial cells.