Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics - Université Pierre et Marie Curie
Journal Articles eLife Year : 2016

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.
Fichier principal
Vignette du fichier
elife-17536.pdf (3.19 Mo) Télécharger le fichier
Origin Publication funded by an institution

Dates and versions

hal-01615584 , version 1 (22-05-2024)

Licence

Identifiers

Cite

Carmen Capone, Fabrice Dabertrand, Céline Baron-Menguy, Athena Chalaris, Lamia Ghezali, et al.. Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. eLife, 2016, 5, ⟨10.7554/eLife.17536⟩. ⟨hal-01615584⟩
100 View
22 Download

Altmetric

Share

More