Contribution of voltage‐gated potassium channels in cerebrovascular dysfunction associated with a genetic model of ischemic small vessel disease (1068.1)

Dominant mutations in the NOTCH3 gene induce the most common heritable cause of stroke and vascular dementia, referred to as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Using a recently developed mouse model of CADASIL (Joutel, JCI, 2010), we examined the consequences of this mutation on the function of intracerebral arterioles. Elevation of intravascular pressure to 20 mm Hg constricted isolated arterioles from control and CADASIL mice to a similar extent. However, above 30 mm Hg, CADASIL arterioles displayed impaired vascular reactivity. At 40 mm Hg, CADASIL arterioles were 38% less constricted, and their smooth muscle membrane potential was 10 mV more hyperpolarized than control. A pharmacologic approach revealed an unchanged activity of small-, intermediate-, large-conductance calcium-sensitive potassium channels. However the voltage-gated potassium (Kv) channel blocker 4-AP enhanced pressure-induced constriction to a greater extent in both par...