Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics
Carmen Capone,
Fabrice Dabertrand,
Celine Baron-Menguy,
Athena Chalaris,
Lamia Ghezali,
Valérie Domenga-Denier,
Stefanie Schmidt,
Clément Huneau,
Stefan Rose-John,
Mark T Nelson,
Anne Joutel
Affiliations
Carmen Capone
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
Fabrice Dabertrand
Department of Pharmacology, University of Vermont, Burlington, United States; College of Medicine, University of Vermont, United States
Celine Baron-Menguy
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
Athena Chalaris
Institute of Biochemistry, Christian Albrechts University, Kiel, Germany; Medical Faculty, Christian Albrechts University, Kiel, Germany
Lamia Ghezali
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
Valérie Domenga-Denier
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
Stefanie Schmidt
Institute of Biochemistry, Christian Albrechts University, Kiel, Germany; Medical Faculty, Christian Albrechts University, Kiel, Germany
Clément Huneau
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
Stefan Rose-John
Institute of Biochemistry, Christian Albrechts University, Kiel, Germany; Medical Faculty, Christian Albrechts University, Kiel, Germany
Mark T Nelson
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
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
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.
