title: Potassium channelopathy-like defect underlies early-stage cerebrovascular dysfunction in a genetic model of small vessel disease.
abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by dominant mutations in the NOTCH3 receptor in vascular smooth muscle, is a genetic paradigm of small vessel disease (SVD) of the brain. Recent studies using transgenic (Tg)Notch3(R169C) mice, a genetic model of CADASIL, revealed functional defects in cerebral (pial) arteries on the surface of the brain at an early stage of disease progression. Here, using parenchymal arterioles (PAs) from within the brain, we determined the molecular mechanism underlying the early functional deficits associated with this Notch3 mutation. At physiological pressure (40 mmHg), smooth muscle membrane potential depolarization and constriction to pressure (myogenic tone) were blunted in PAs from TgNotch3(R169C) mice. This effect was associated with an ∼ 60% increase in the number of voltage-gated potassium (KV) channels, which oppose pressure-induced depolarization. Inhibition of KV1 channels with 4-aminopyridine (4-AP) or treatment with the epidermal growth factor receptor agonist heparin-binding EGF (HB-EGF), which promotes KV1 channel endocytosis, reduced KV current density and restored myogenic responses in PAs from TgNotch3(R169C) mice, whereas pharmacological inhibition of other major vasodilatory influences had no effect. KV1 currents and myogenic responses were similarly altered in pial arteries from TgNotch3(R169C) mice, but not in mesenteric arteries. Interestingly, HB-EGF had no effect on mesenteric arteries, suggesting a possible mechanistic basis for the exclusive cerebrovascular manifestation of CADASIL. Collectively, our results indicate that increasing the number of KV1 channels in cerebral smooth muscle produces a mutant vascular phenotype akin to a channelopathy in a genetic model of SVD.
authors: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405;
authors: Fabrice
authors: F
authors: Dabertrand
authors: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405;
authors: Christel
authors: C
authors: Krøigaard
authors: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405;
authors: Adrian D
authors: AD
authors: Bonev
authors: INSERM, U1161 and Université Paris Diderot, Sorbonne Cité, UMR S1161, Paris, F-75010, France; and.
authors: Emmanuel
authors: E
authors: Cognat
authors: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405;
authors: Thomas
authors: T
authors: Dalsgaard
authors: INSERM, U1161 and Université Paris Diderot, Sorbonne Cité, UMR S1161, Paris, F-75010, France; and.
authors: Valérie
authors: V
authors: Domenga-Denier
authors: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405;
authors: David C
authors: DC
authors: Hill-Eubanks
authors: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405;
authors: Joseph E
authors: JE
authors: Brayden
authors: INSERM, U1161 and Université Paris Diderot, Sorbonne Cité, UMR S1161, Paris, F-75010, France; and.
authors: Anne
authors: A
authors: Joutel
authors: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405; Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, United Kingdom Mark.Nelson@uvm.edu.
authors: Mark T
authors: MT
authors: Nelson
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000503:physiopathology*; D002561:Cerebrovascular Disorders / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D066257:Heparin-binding EGF-like Growth Factor / Q000502:physiology; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D015221:Potassium Channels / Q000235:genetics*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology
chemical_list: C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; C499373:Notch3 protein, mouse; D015221:Potassium Channels; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D015761:4-Aminopyridine
keywords: CADASIL; cerebral small vessel disease; channelopathy; vascular smooth muscle cells; voltage-gated potassium channel
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