Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: Molecular and pharmacologic characterization

Physiologic and anatomic evidence suggest that 5-hydroxytryptamine (5-HT) n eurons regulate local cerebral blood flow and blood-brain barrier permeabil ity. To evaluate the possibility that some of these effects occur directly on the blood vessels, molecular and/or pharmacologic approaches were used t o assess the presence of 5-HT receptors in human brain microvascular fracti ons, endothelial and smooth muscle cell cultures, as well as in astroglial cells which intimately associate with intraparenchymal blood vessels. isola ted microvessels and capillaries consistently expressed messages for the h5 -HT1B, h5-HT1D, 5-HT1F, 5-HT2A but not 5-MT7 receptors. When their distribu tion within the vessel wall was studied in mon detail, it was found that ca pillary endothelial cells exhibited mRNA for the h5-HT1D and for the 5-HT7 receptors whereas microvascular smooth muscle cells, in addition to h5-HT1D and 5-HT7, also showed polymerase chain reaction products for h5-HT1B rece ptors. Expression of 5-HT1F and 5-HT2A receptor mRNAs was never detected in any of the microvascular cell cultures. In contrast, messages for all 5-HT receptors tested were detected in human brain astrocytes with a predominan ce of the 5-HT2A and 5-HT7 subtypes. In all cultures, sumatriptan inhibited (35-58%, P < .05) the forskolin-stimulated production of cyclic AMP, an ef fect blocked by the 5-HT1B/1D receptor antagonists GR127935 and GR55562. In contrast, 5-carboxamidotryptamine induced strong increases (greater than o r equal to 400%, P < .005) in basal cyclic AMP levels that were abolished b y mesulergine, a nonselective 5-HT7 receptor antagonist. Only astroglial ce lls showed a ketanserin-sensitive increase (177%, P < .05) in IP3 formation when exposed to 5-HT. These results show that specific populations of func tional 5-HT receptors are differentially distributed within the various cel lular compartments of the human cortical microvascular bed, and that human brain astroglial cells are endowed with multiple 5-HT receptors. These find ings emphasize the complex interactions between brain serotonergic pathways and non-neuronal cells within the CNS and, further, they raise the possibi lity that some of these receptors may be activated by antimigraine compound s such as brain penetrant triptan derivatives.