Calcium‐sensitive potassium channels are not involved in the decreased myogenic tone of posterior cerebral arteries in a genetic model of cerebral ischemic small vessel disease

Abstract

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an archetypal monogenetic form of small vessel disease (SVD) of the brain. In a novel transgenic mouse model for CADASIL (R169C), a compromised cerebral blood flow and neurovascular coupling has been shown. This study investigates the consequences of CADASIL on the relationship between intravascular pressure and diameter and the function of potassium (K+) channels in isolated posterior cerebral arteries (PCAs). Elevation of intravascular pressure to 60 mmHg resulted in 38% reduced constriction of isolated CADASIL PCAs. However, vasodilation to NS309, an activator of endothelial small (SK) and intermediate (IK) conductance Ca2+‐sensitive K+ (KCa) channels, was unaffected. In addition, blocking SK, IK and smooth muscle large conductance calcium (Ca2+)‐sensitive (BK) channels constricted CADASIL PCAs to the same extent as control PCAs. In contrast, the vasoconstriction induced by heparin‐binding epidermal growth factor (HB‐EGF), that causes voltage‐dependent K+ (KV) channel endocytosis via activation of EGF, was decreased in CADASIL PCAs. In conclusion, KCa channel function is conserved in PCAs from CADASIL mice, whereas KV channel up‐regulation may play a critical role in the decreased myogenic tone observed. Supported by NIH PO1HL095488, Fondation Leducq and The Lundbeck Foundation.