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Alzheimer's disease and cerebrovascular pathology alter inward rectifier potassium (K IR 2.1) channels in endothelium of mouse cerebral arteries
Author(s) -
LacalleAurioles María,
Trigiani Lianne J.,
Bourourou Miled,
Lecrux Clotilde,
Hamel Edith
Publication year - 2022
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15751
Subject(s) - oxidative stress , inflammation , potassium channel , inward rectifier potassium ion channel , cerebral arteries , vasodilation , chemistry , endothelial dysfunction , medicine , endocrinology , genetically modified mouse , pharmacology , pathology , biochemistry , transgene , ion channel , receptor , gene
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.