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.DOI: http://dx.doi.org/10.7554/eLife.17536.001

The yin and yang of KV channels in cerebral small vessel pathologies

“…In the hemorrhagic stroke (ie, SAH) model, MMP activation is understood to cause K V channel endocytosis through activation of the EGFR, resulting in increased vasoconstriction and decreased CBF . On the other hand, in a mouse model of CADASIL, an increase in TIMP‐3 inhibits MMP (ADAM17) activity, leading to an increased number of functional K V channels in the plasma membrane of arteriolar SMCs and attenuation of vasoconstriction . These findings support the concept that the number of K V channels is tuned to provide the appropriate membrane potential control in response to changes in intravascular pressure, and that any change in channel number will adversely affect cerebral arteriolar function.…”

“…These deficits appear to be driven by changes in the balance of MMP activity which supports the novel concept that perturbations of the extracellular matrix can be a point of convergence between these cerebral small vessel pathologies . These changes, in turn, alter the number of voltage‐gated K + ( K V ) channels at the arteriolar SMCs plasma membrane . The K V channel superfamily, comprising 12 subfamilies ( K V 1– K V 12), is one of the most diverse families of K + channels identified to date .…”

“…In both SAH and CADASIL, dysregulation of brain PA reactivity precedes the onset of neurological deficits. Using well‐established rabbit, rat, and mouse models of SAH, and a transgenic mouse model of CADASIL (TgNotch3 R169C ) in which a human NOTCH3 receptor mutation—the molecular cause of CADASIL—is overexpressed, we have discovered that K V channel activity in PA SMCs is abnormal in both pathological conditions . Although abnormal K V activity could conceivably reflect changes in channel gating properties or recruitment of new K V channel family members, our experimental data demonstrated unchanged τ act , V 0.5 , or k in both disease models.…”

“…One possible mechanism underlying both of these vascular pathologies is altered trafficking of K V channels. In this context, altered shedding of the EGFR ligand, HB‐EGF, caused by aberrant MMP and/or ADAM activity, leads to enhanced (SAH) or decreased (CADASIL) EGFR‐mediated endocytosis of K V channels …”

Sorsby fundus dystrophy: Insights from the past and looking to the future

“…It has recently been shown that mutant NOTCH3‐ECD interacts with TIMP3 (and other ECM proteins) promoting the accumulation of TIMP3 in those deposits (Monet‐Lepretre et al, ). There is evidence that the increased amounts of TIMP3 retaining its MMP inhibitory activity contribute to CADASIL pathophysiology since haploinsufficiency of Timp3 in mice rescues reduced cerebrovascular reactivity, one of CADASIL‐related phenotypic features (Capone et al, ). Thus, elevated levels of extracellular TIMP3 also seem to be crucial for small vessel disease.…”