Affiliations: [a] National Ageing Research Institute, Department of Medicine, University Of Melbourne, P.O. Box 31, Parkville Victoria, Australia 3052 | [b] Department of Pathology, University of Melbourne, Parkville Victoria, Australia 3052 | [c] Mental Health Research Institute, Parkville Victoria, Australia 3052 | [d] University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany
Correspondence:
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Corresponding author: A/Pr. Zeinab Khalil, National Ageing Research Institute, Poplar Rd, PO Box 31, Parkville, Victoria, Australia, 3052. Tel.: +61 3 8387 2148; Fax: +61 3 9387 4030; E-mail: z.khalil@nari.unimelb.edu.au.
Abstract: Freshly prepared soluble amyloid (Aβ) peptide has been reported to have vascular actions both in vitro and in vivo. This study was designed to examine the in vivo microvascular effects ofβ in two skin microvascular model systems that might reflect possible short and long-term vascular effects of this peptide. Short-term vascular effects were examined using freshly prepared soluble Aβ(1-40) peptide superfused over naive rat skin microvasculature for 15 min. Peripheral microvascular functional changes in 9-months-old transgenic (Tg) mice overexpressing solubleβ in the brain, peripheral circulation and other tissues, were also examined. Microvascular responses were monitored using laser Doppler flowmetry from the base of a blister raised on the hind footpad of the animals. Endothelial-dependent and independent vasodilatation responses (VD) were examined using acetylcholine (ACh) and sodium nitroprusside (SNP) respectively. The exposure of naïve rat skin microvasculature to Aβ(1-40) resulted in an immediate vasoconstriction (VC) that prevented ACh but not SNP from inducing a subsequent VD response. The vascular effects of Aβ(1-40) were reversed by antioxidants (superoxide dismutase and catalase) and an endothelin A (ETA) receptor antagonist (BQ-123). Tg mice overexpressing soluble Aβ and C100 showed significant reductions in both endothelial-dependent and endothelial-independent VD that were also reversed by antioxidants and BQ-123. In conclusion, this study provided evidence to support the notion of peripheral vascular effects of Aβ in vivo and present novel evidence for alterations in endothelial and smooth muscle cell function in peripheral skin microvasculature in Tg mice overexpressing Aβ and C100. We suggest that skin microvasculature is a useful model to examine the mechanisms underlying the vascular actions of the Aβ protein.
