Figure 8. Proposed model of TIMP3 regulation of cerebral arterial tone and CBF responses.
(A) Under physiological conditions (upper panel), TIMP3 is present in a low abundance in the extracellular matrix of brain arteries. ADAM17 at the cell surface of cerebral arterial myocytes is therefore active and able to cleave and release sHB-EGF, resulting in ErbB1/ErbB4 activation and KV1 channel endocytosis. The internalization of KV1 channels relieves the tonic hyperpolarizing influence of these channels on the membrane potential of arterial myocytes, thereby allowing full development of pressure-induced vasoconstriction (myogenic tone) of brain arteries and enabling full CBF responses to whisker stimulation and vasodilators. (B) In CADASIL (lower panel), Notch3ECD accumulates at the surface of smooth muscle cells, leading to an increase in the amount of TIMP3, which binds to and inhibits ADAM17, blunting sHB-EGF release and ErbB1/ErbB4 activity, and thereby decreasing KV1 endocytosis. The resulting increase in KV1 current density hyperpolarizes arterial myocytes, acting as a brake to limit the development of myogenic tone and evoked CBF responses.