Crawford F, Suo Z, Fang C, Mullan M
Roskamp Laboratory, Department of Psychiatry, University of South Florida, Tampa 33613, USA.
Exp Neurol. 1998 Mar;150(1):159-68. doi: 10.1006/exnr.1997.6743.
The beta-amyloid (A beta 1-40) peptide has previously been shown to enhance phenylephrine contraction of aortic rings in vitro. We have employed a novel observation, that A beta peptides enhance endothelin-1 (ET-1) contraction, to examine the relationship between vasoactivity and potential amyloidogenicity of A beta peptides, the role played by free radicals and calcium in the vasoactive mechanism, and the requirement of an intact endothelial layer for enhancement of vasoactivity. Rings of rat aortae were constricted with ET-1 before and after addition of amyloid peptide and/or other compounds, and a comparison was made between post- and pre-treatment contractions. In this system, vessel constriction is consistently dramatically enhanced by A beta 1-40, is enhanced less so by A beta 1-42, and is not enhanced by A beta 25-35. The endothelium is not required for A beta vasoactivity, and calcium channel blockers have a greater effect than antioxidants in blocking enhancement of vasoconstriction by A beta peptides. In contrast to A beta-induced cytotoxicity, A beta-induced vasoactivity is immediate, occurs in response to low doses of freshly solubilized peptide, and appears to be inversely related to the amyloidogenic potential of the A beta peptides. We conclude that the mechanism of A beta vasoactivity is distinct from that of A beta cytotoxicity. Although free radicals appear to modulate the vasoactive effects, the lack of requirement for endothelium suggests that loss of the free radical balance (between NO and O2-) may be a secondary influence on A beta enhancement of vasoconstriction. These effects of A beta on isolated vessels, and reported effects of A beta in cells of the vasculature, suggest that A beta-induced disruption of vascular tone may be a factor in the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. Although the mechanism of enhanced vasoconstriction is unknown, it is reasonable to propose that in vivo contact of A beta peptides with small cerebral vessels may increase their tendency to constrict and oppose their tendency to relax. The subclinical ischemia resulting from this would be expected to up-regulate beta APP production in and around the vasculature with further increase in A beta formation and deposition. The disruptive and degenerative effects of such a cycle would lead to the complete destruction of cerebral vessels and consequently neuronal degeneration in the affected areas.
先前已表明，β-淀粉样蛋白（Aβ1-40）肽在体外可增强去氧肾上腺素对主动脉环的收缩作用。我们采用了一项新的观察结果，即Aβ肽可增强内皮素-1（ET-1）的收缩作用，以研究Aβ肽的血管活性与潜在淀粉样变性之间的关系、自由基和钙在血管活性机制中所起的作用，以及完整内皮细胞层对增强血管活性的必要性。在添加淀粉样肽和/或其他化合物之前和之后，用ET-1使大鼠主动脉环收缩，并对处理后和处理前的收缩情况进行比较。在该系统中，Aβ1-40可持续显著增强血管收缩，Aβ1-42的增强作用较小，而Aβ25-35则无增强作用。Aβ的血管活性不需要内皮细胞，并且钙通道阻滞剂在阻断Aβ肽增强血管收缩方面比抗氧化剂的作用更大。与Aβ诱导的细胞毒性相反，Aβ诱导的血管活性是即时的，在低剂量新鲜溶解的肽作用下即可发生，并且似乎与Aβ肽的淀粉样变性潜力呈负相关。我们得出结论，Aβ的血管活性机制与Aβ的细胞毒性机制不同。尽管自由基似乎可调节血管活性作用，但对内皮细胞的不需要表明自由基平衡（一氧化氮和超氧阴离子之间）的丧失可能是Aβ增强血管收缩的次要影响因素。Aβ对离体血管的这些作用，以及报道的Aβ在血管系统细胞中的作用，表明Aβ诱导的血管张力破坏可能是脑淀粉样血管病和阿尔茨海默病发病机制中的一个因素。尽管血管收缩增强的机制尚不清楚，但合理的推测是，Aβ肽在体内与脑小血管接触可能会增加其收缩倾向并抑制其舒张倾向。由此导致的亚临床缺血预计会上调血管及其周围β-淀粉样前体蛋白（βAPP）的产生，从而进一步增加Aβ的形成和沉积。这样一个循环的破坏和退化作用将导致脑血管的完全破坏，进而导致受影响区域的神经元变性。
