Abstract
BACKGROUND AND PURPOSE: Inward rectifier potassium (K(IR) ) channels are key effectors of vasodilatation in neurovascular coupling (NVC). K(IR) channels expressed in cerebral endothelial cells (ECs) have been confirmed as essential modulators of NVC. Alzheimer's disease (AD) and cerebrovascular disease (CVD) impact on EC-K(IR) channel function, but whether oxidative stress or inflammation explains this impairment remains elusive. EXPERIMENTAL APPROACH: We evaluated K(IR) channel function in intact and EC-denuded pial arteries of wild-type (WT) and transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APP mice, recapitulating amyloid β-induced oxidative stress seen in AD) or a constitutively active form of TGF-β1 (TGF mice, recapitulating inflammation seen in cerebrovascular pathology). The benefits of antioxidant (catalase) or anti-inflammatory (indomethacin) drugs also were investigated. Vascular and neuronal components of NVC were assessed in vivo. KEY RESULTS: Our findings show that (i) K(IR) channel-mediated maximal vasodilatation in APP and TGF mice reaches only 37% and 10%, respectively, of the response seen in WT mice; (ii) K(IR) channel dysfunction results from K(IR) 2.1 subunit impairment; (iii) about 50% of K(+) -induced artery dilatation is mediated by EC-K(IR) channels; (iv) oxidative stress and inflammation impair K(IR) channel function, which can be restored by antioxidant and anti-inflammatory drugs; and (v) inflammation induces K(IR) 2.1 overexpression and impairs NVC in TGF mice. CONCLUSION AND IMPLICATIONS: Therapies targeting both oxidative stress and inflammation are necessary for full recovery of K(IR) 2.1 channel function in cerebrovascular pathology caused by AD and CVD.