Assignment of ecto-nucleoside triphosphate diphosphohydrolase-1/cd39 expression to microglia and vasculature of the brain

Extracellular nucleotides are ubiquitous extracellular mediators that inter act with and activate nucleotide type 2 (P2) receptors. These receptors ini tiate a wide variety of signalling pathways that appear important for funct ional associations between neurons and glial cells and for the regulation o f blood flow, haemostatic and inflammatory reactions in the brain. Ectonucl eotidases are extracellular nucleotide-metabolizing enzymes that modulate P 2 receptor-mediated signalling by the regulated hydrolysis of these agonist s. A considerable number of ectoenzyme species with partially overlapping s ubstrate and tissue distributions have been described. Major candidates for expression in the brain are members of the ecto-nucleoside triphosphate di phosphohydrolase (E-NTPDase or CD39) family. The production of cd39(-/-) mi ce and specific reagents have enabled us to analyse the specific cellular d istribution of NTPDase1 (CD39), the prototype member of the enzyme family, in the mouse brain. Using monospecific antibodies and enzyme histochemical staining, we have identified NTPDase1 as a major ectonucleotidase associate d with both microglia and the endothelial and smooth muscle cells of the va sculature. NTPDase1 is not expressed by neurons and astrocytes. Additional unidentified ectonucleotidase functional activity is observed at lower leve ls throughout the brain parenchyma. NTPDase1 may regulate P2 receptor-media ted functions of microglia as well as influence nucleotide signalling betwe en neurons or astrocytes that are associated with multiple microglial ramif ications. The expression of NTPDase1 by cerebrovascular endothelial and smo oth muscle cells also suggests involvement in the regulation of blood flow and thrombogenesis.