title: Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics.
abstract: Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor of metalloproteinase 3) accumulation in the vascular extracellular matrix in CADASIL is a key contributor to cerebrovascular dysfunction. However, the linkage between elevated TIMP3 and compromised cerebral blood flow (CBF) remains unknown. Here, we show that TIMP3 acts through inhibition of the metalloprotease ADAM17 and HB-EGF to regulate cerebral arterial tone and blood flow responses. In a clinically relevant CADASIL mouse model, we show that exogenous ADAM17 or HB-EGF restores cerebral arterial tone and blood flow responses, and identify upregulated voltage-dependent potassium channel (KV) number in cerebral arterial myocytes as a heretofore-unrecognized downstream effector of TIMP3-induced deficits. These results support the concept that the balance of TIMP3 and ADAM17 activity modulates CBF through regulation of myocyte KV channel number.
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, U1161, Université Paris Diderot, Sorbonne Paris Cité, UMRS 1161, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Capone
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, United States.|College of Medicine, University of Vermont, United States.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Dabertrand
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, U1161, Université Paris Diderot, Sorbonne Paris Cité, UMRS 1161, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Baron-Menguy
authors.affiliation: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.|Medical Faculty, Christian Albrechts University, Kiel, Germany.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, U1161, Université Paris Diderot, Sorbonne Paris Cité, UMRS 1161, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Lamia
authors.initials: L
authors.lastname: Ghezali
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, U1161, Université Paris Diderot, Sorbonne Paris Cité, UMRS 1161, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Domenga-Denier
authors.affiliation: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.|Medical Faculty, Christian Albrechts University, Kiel, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, U1161, Université Paris Diderot, Sorbonne Paris Cité, UMRS 1161, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Huneau
authors.affiliation: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.|Medical Faculty, Christian Albrechts University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, United States.|College of Medicine, University of Vermont, United States.|Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, U1161, Université Paris Diderot, Sorbonne Paris Cité, UMRS 1161, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Anne
authors.identifier: 0000-0003-3963-3860
authors.initials: A
authors.lastname: Joutel
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000502:physiology*; D046589:CADASIL / Q000503:physiopathology*; D004195:Disease Models, Animal; D006439:Hemodynamics; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism*; D051379:Mice; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D024642:Potassium Channels, Voltage-Gated; D019717:Tissue Inhibitor of Metalloproteinase-3; D000072198:ADAM17 Protein
keywords: ADAM17; CADASIL; cerebral blood flow; cerebral small vessel disease; human biology; medicine; mouse; myogenic tone; neuroscience; voltage-gated potassium channel