ArticleProceedings of the National Academy of Sciences of the United States of America2015
Potassium channelopathy-like defect underlies early-stage cerebrovascular dysfunction in a genetic model of small vessel disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 1 of them a synthesis that pooled it.
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Who cites it
60 citing papers in PubMed, 1 synthesis or guideline pooled it, 97 citations in OpenAlex.
- A genome-wide association meta-analysis of all-cause and vascular dementia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Pooled it
- Pericyte KNature cardiovascular research · 2026Article
- Potassium channels in vascular smooth muscle cells.Physiological reviews · 2026Review
- Pervasive neurovascular dysfunction in the ventromedial prefrontal cortex of female depressed suicides with a history of childhood abuse.Molecular psychiatry · 2026Article
- Intracerebral age-independent reduction of endothelium-dependent hyperpolarization and nitric oxide signalling in the Dp16 mouse model of Down syndrome.The Journal of physiology · 2026Article
- A theoretical model for oxygen transport to the cerebral cortex: effects of flow redistribution by penetrating arterioles.Microvascular research · 2025Article
- Estrogen Enhances SK Channel Activity to Limit Hippocampal Arteriole Constriction.Circulation research · 2025Article
- The pathogenesis of cerebral small vessel disease and vascular cognitive impairment.Physiological reviews · 2025Review
- The Pathobiology of Cerebrovascular Lesions in CADASIL Small Vessel Disease.Basic & clinical pharmacology & toxicology · 2025Review
- Pericyte Electrical Signalling and Brain Haemodynamics.Basic & clinical pharmacology & toxicology · 2025Review
- Increased luminal pressure in brain capillaries drives TRPC3-dependent depolarization and constriction of transitional pericytes.Science signaling · 2025Article
- Article
- Depth-dependent contributions of various vascular zones to cerebral autoregulation and functional hyperemia: An in-silico analysis.PloS one · 2025Article
- CADASIL: A NOTCH3-associated cerebral small vessel disease.Journal of advanced research · 2024Review
- Distinct potassium channel types in brain capillary pericytes.Biophysical journal · 2024Article
- Pathophysiology of cerebral small vessel disease: a journey through recent discoveries.The Journal of clinical investigation · 2024Review
- Analysis of potassium ion diffusion from neurons to capillaries: Effects of astrocyte endfeet geometry.The European journal of neuroscience · 2024Article
- Impaired intracellular CaScience signaling · 2023Article
- Epidermal Growth Factor Receptors in Vascular Endothelial Cells Contribute to Functional Hyperemia in the Brain.International journal of molecular sciences · 2023Article
- PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
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.
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