Fiona Crawford1, Zhiming Suo, Chunhong Fang and Mike Mullan
Roskamp Laboratories, Department of Psychiatry, 3515 East Fletcher Avenue, University of South Florida, Tampa, Florida, 33613
The β-amyloid (Aβ1–40) peptide has previously been shown to enhance phenylephrine contraction of aortic ringsin vitro.We have employed a novel observation, that Aβ peptides enhance endothelin-1 (ET-1) contraction, to examine the relationship between vasoactivity and potential amyloidogenicity of Aβ 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 pretreatment contractions. In this system, vessel constriction is consistently dramatically enhanced by Aβ1–40, is enhanced less so by Aβ1–42, and is not enhanced by Aβ25–35. The endothelium isnotrequired for Aβ vasoactivity, and calcium channel blockers have a greater effect than antioxidants in blocking enhancement of vasoconstriction by Aβ peptides. In contrast to Aβ-induced cytotoxicity, Aβ-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 Aβ peptides. We conclude that the mechanism of Aβ vasoactivity is distinct from that of Aβ 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 O−2) may be a secondary influence on Aβ enhancement of vasoconstriction. These effects of Aβ on isolated vessels, and reported effects of Aβ in cells of the vasculature, suggest that Aβ-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 thatin vivocontact of Aβ 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 βAPP production in and around the vasculature with further increase in Aβ 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.
Author Keywords: β-amyloid; vasoactivity; Alzheimer’s disease; cerebral amyloid angiopathy; endothelin-1.