Long-term incubation with β-amyloid peptides impairs endothelium-dependent vasodilatation in isolated rat basilar artery

Abstract

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 β-amyloid (Aβ) peptides to isolated vessels affects vascular tone within 1 h, but no studies have examined the effect of long-term incubation with Aβ. Here we evaluate the effect of Aβ (1–40) and Aβ (25–35) in rat basilar artery for up to 24 h. Basilar artery segments were incubated with 25 μM Aβ (1–40) or Aβ (25–35), for 6 or 24 h. After treatment, arteries were mounted in a wire myograph, in physiological salt solution gassed with O 2/CO 2, in the absence of Aβ, and challenged with vasoconstrictors and vasodilators. Vasomotor responses were not significantly changed by 6 h treatment with Aβ peptides whereas 24 h treatment with either Aβ (25–35) or Aβ (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 Aβ 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.