Cohen Z, Bouchelet I, Olivier A, Villemure J G, Ball R, Stanimirovic D B, Hamel E
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montréal, Québec, Canada.
J Cereb Blood Flow Metab. 1999 Aug;19(8):908-17. doi: 10.1097/00004647-199908000-00010.
Physiologic and anatomic evidence suggest that 5-hydroxytryptamine (5-HT) neurons regulate local cerebral blood flow and blood-brain barrier permeability. To evaluate the possibility that some of these effects occur directly on the blood vessels, molecular and/or pharmacologic approaches were used to assess the presence of 5-HT receptors in human brain microvascular fractions, endothelial and smooth muscle cell cultures, as well as in astroglial cells which intimately associate with intraparenchymal blood vessels. Isolated microvessels and capillaries consistently expressed messages for the h5-HT1B, h5-HT1D, 5-HT1F, 5-HT2A but not 5-HT7 receptors. When their distribution within the vessel wall was studied in more detail, it was found that capillary 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 receptors. 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 predominance 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 effect blocked by the 5-HT1B/1D receptor antagonists GR127935 and GR55562. In contrast, 5-carboxamidotryptamine induced strong increases (> or = 400%, P < .005) in basal cyclic AMP levels that were abolished by mesulergine, a nonselective 5-HT7 receptor antagonist. Only astroglial cells showed a ketanserin-sensitive increase (177%, P < .05) in IP3 formation when exposed to 5-HT. These results show that specific populations of functional 5-HT receptors are differentially distributed within the various cellular compartments of the human cortical microvascular bed, and that human brain astroglial cells are endowed with multiple 5-HT receptors. These findings emphasize the complex interactions between brain serotonergic pathways and non-neuronal cells within the CNS and, further, they raise the possibility that some of these receptors may be activated by antimigraine compounds such as brain penetrant triptan derivatives.
生理学和解剖学证据表明，5-羟色胺（5-HT）神经元调节局部脑血流量和血脑屏障通透性。为了评估这些效应中某些是否直接作用于血管，采用分子和/或药理学方法评估人脑微血管组分、内皮细胞和平滑肌细胞培养物以及与脑实质内血管紧密相连的星形胶质细胞中5-HT受体的存在情况。分离的微血管和毛细血管始终表达h5-HT1B、h5-HT1D、5-HT1F、5-HT2A受体的信息，但不表达5-HT7受体。当更详细地研究它们在血管壁内的分布时，发现毛细血管内皮细胞表达h5-HT1D和5-HT7受体的mRNA，而微血管平滑肌细胞除了h5-HT1D和5-HT7受体外，还显示h5-HT1B受体的聚合酶链反应产物。在任何微血管细胞培养物中均未检测到5-HT1F和5-HT2A受体mRNA的表达。相反，在人脑星形胶质细胞中检测到所有测试的5-HT受体的信息，其中5-HT2A和5-HT7亚型占优势。在所有培养物中，舒马曲坦抑制（35 - 58%，P <.05）福司可林刺激的环磷酸腺苷生成，5-HT1B/1D受体拮抗剂GR-127935和GR-55562可阻断该效应。相反，5-羧酰胺色胺使基础环磷酸腺苷水平大幅升高（≥400%，P <.005），非选择性5-HT7受体拮抗剂美舒麦角可消除该升高。仅星形胶质细胞在暴露于5-HT时显示对酮色林敏感的肌醇三磷酸生成增加（177%，P <.05）。这些结果表明，功能性5-HT受体的特定群体在人皮质微血管床的不同细胞区室中差异分布，并且人脑星形胶质细胞具有多种5-HT受体。这些发现强调了脑血清素能途径与中枢神经系统内非神经元细胞之间复杂的相互作用，此外，它们还增加了某些这些受体可能被抗偏头痛化合物如可穿透脑的曲坦衍生物激活的可能性。
