Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
Pharmacol Res. 2010 Feb;61(2):157-61. doi: 10.1016/j.phrs.2009.09.004. Epub 2009 Sep 24.
Alzheimer's disease is associated to a cerebral amyloid angiopathy with dysregulation of cerebral blood flow (CBF). In vitro studies have shown that short-term application of beta-amyloid (Abeta) peptides to isolated vessels affects vascular tone within 1h, but no studies have examined the effect of long-term incubation with Abeta. Here we evaluate the effect of Abeta((1-40)) and Abeta((25-35)) in rat basilar artery for up to 24h. Basilar artery segments were incubated with 25microeta((1-40)) or Abeta((25-35)), for 6 or 24h. After treatment, arteries were mounted in a wire myograph, in physiological salt solution gassed with O(2)/CO(2), in the absence of Abeta, and challenged with vasoconstrictors and vasodilators. Vasomotor responses were not significantly changed by 6h treatment with Abeta peptides whereas 24h treatment with either Abeta((25-35)) or Abeta((1-40)) increased vasoconstriction to 5-hydroxytryptamine (5-HT) and reduced endothelium-dependent vasodilatation to acetylcholine (ACh). Analysis of endothelial cells did not show apoptotic changes associated to endothelial dysfunction, as assessed by TUNEL immunostaining and examination of nuclear morphology, but basal phosphorylation of endothelial nitric oxide synthase (at serine 1177) appeared reduced. These data suggest that long incubation with Abeta peptides induces an alteration of endothelial function in isolated basilar artery, involving eNOS activity without changing cell morphology. This endothelial dysfunction may play a role in the pathogenesis of CBF dysregulation occurring in cerebral amyloid angiopathy and Alzheimer's disease.
阿尔茨海默病与脑淀粉样血管病相关，伴有脑血流（CBF）调节紊乱。体外研究表明，β-淀粉样肽（Abeta）短时间应用于分离的血管会在 1 小时内影响血管张力，但尚无研究检测 Abeta 长时间孵育的影响。在此，我们评估 Abeta((1-40))和 Abeta((25-35))在大鼠基底动脉中的作用，最长达 24 小时。用 25microeta((1-40))或 Abeta((25-35))孵育基底动脉段 6 或 24 小时。处理后，将动脉置于含氧量/二氧化碳量的生理盐溶液中的金属丝肌动描记器中，无 Abeta 存在，并以血管收缩剂和血管扩张剂进行挑战。Abeta 肽 6 小时处理对血管舒缩反应没有显著影响，而 Abeta((25-35))或 Abeta((1-40))处理 24 小时则增加了对 5-羟色胺（5-HT）的血管收缩反应，并降低了对乙酰胆碱（ACh）的内皮依赖性血管舒张反应。TUNEL 免疫染色和核形态检查未显示与内皮功能障碍相关的细胞凋亡变化，分析内皮细胞，但其基础一氧化氮合酶（丝氨酸 1177 处）的磷酸化似乎减少。这些数据表明，Abeta 肽长时间孵育会引起分离的基底动脉内皮功能障碍改变，涉及内皮型一氧化氮合酶（eNOS）活性，而不改变细胞形态。这种内皮功能障碍可能在脑淀粉样血管病和阿尔茨海默病中发生的 CBF 调节紊乱的发病机制中起作用。
