Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics.

Carmen Capone,Clément Huneau,Mark T Nelson,Fabrice Dabertrand,Anne Joutel,Lamia Ghezali,Celine Baron-Menguy,Stefanie Schmidt,Stefan Rose-John,Valérie Domenga-Denier,Athena Chalaris

doi:10.7554/elife.17536

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.

Highlights

Small vessel disease (SVD) of the brain is a leading cause of stroke and age-related cognitive decline and disability for which there are currently no treatments (Pantoni, 2010)
We found that TIMP3 (40 nM) did not affect resting cerebral blood flow (CBF) (Figure 1B), but did strongly reduce the increase in CBF evoked by whisker stimulation (Figure 1C, D; Figure 1—source data 2,3)
SVD of the brain is a heterogeneous group of disorders with different ultimate causes acting through specific pathways, the recently emerging view is that perturbations of proteins constituting or associated with the extracellular matrix of cerebral vessels could be a convergent pathway driving the functional and structural alterations of small brain vessels (Joutel et al, 2016)

Summary

Introduction

Small vessel disease (SVD) of the brain is a leading cause of stroke and age-related cognitive decline and disability for which there are currently no treatments (Pantoni, 2010). Our limited understanding of the pathogenesis of cerebral SVD is a major obstacle to the development of treatments. Monogenic forms of these diseases, such as CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), provide a window into the mechanism underlying much more common, but largely indistinguishable, sporadic forms of SVD (Joutel and Faraci, 2014). CADASIL, the most common hereditary cerebral SVD, is caused by dominant mutations in the NOTCH3 receptor that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3ECD) and aggregates of other proteins on vessels (Joutel et al, 2000; Chabriat et al, 2009; Monet-Lepretre et al, 2013).

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