Potassium channelopathy-like defect underlies early-stage cerebrovascular dysfunction in a genetic model of small vessel disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-02, Vol.112 (7), p.E796-E805
• Main Authors: Dabertrand, Fabrice, Krøigaard, Christel, Bonev, Adrian D., Cognat, Emmanuel, Dalsgaard, Thomas, Domenga-Denier, Valérie, Hill-Eubanks, David C., Brayden, Joseph E., Joutel, Anne, Nelson, Mark T.
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine - pharmacology; animal models; Animals; arterioles; autoregulation; Binding sites; Biological Sciences; blood flow; Brain; Brain - blood supply; Brain - physiopathology; Cells; central nervous system diseases; Cerebrovascular Disorders - genetics; Cerebrovascular Disorders - physiopathology; Coronary vessels; disease course; Disease Models, Animal; Genotype & phenotype; Heparin-binding EGF-like Growth Factor - physiology; Membrane Potentials; Mice; Mice, Transgenic; Mutation; pathogenesis; physiological response; PNAS Plus; potassium; potassium channels; Potassium Channels - genetics; Receptor, Notch3; Receptors, Notch - genetics; Receptors, Notch - physiology; Rodents; stroke; Vein & artery diseases
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1420765112

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)Notch3R169Cmice, 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 thisNotch3mutation. At physiological pressure (40 mmHg), smooth muscle membrane potential depolarization and constriction to pressure (myogenic tone) were blunted in PAs from TgNotch3R169Cmice. 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 KVcurrent density and restored myogenic responses in PAs from TgNotch3R169Cmice, whereas pharmacological inhibition of other major vasodilatory influences had no effect. KV1 currents and myogenic responses were similarly altered in pial arteries from TgNotch3R169Cmice, 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.