Ion channel dysfunction in small vessel disease of the brain

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PROJECT SUMMARY Cerebral blood flow (CBF) is exquisitely controlled to meet the diverse and ever-changing demands of active neurons. Blood flow into the brain is mediated by penetrating/parenchymal arterioles and hundreds of miles of capillaries, which enormously extend the territory of perfusion. Blood delivery to active neurons (functional hyperemia) is rapidly and precisely controlled through a process termed neurovascular coupling (NVC). We recently provided compelling evidence that brain capillaries act as a neural activity-sensing network, and therefore are much more than simple conduits for blood. This concept explains the rapid and coordinated delivery of blood to active neurons, demonstrating that brain capillary endothelial cells (cECs) are capable of initiating an electrical (hyperpolarizing) signal in response to neural activity that rapidly propagates upstream to cause dilation of feeding arterioles and locally increase blood flow. We have established the mechanistic basis for this electrical signal, showing that neuron- and/or astrocyte-derived potassium (K+) is the critical mediator and identifying the strong inward rectifier K+ channel, Kir2.1, as the key molecular player. We have recently discovered a second fundamental NVC mechanism based on calcium (Ca2+) signaling, which is initiated by Gq-protein coupled receptor signaling and is partly mediated by TRPV4 channels. Dynamic changes in membrane phosphatidylinositol 4,5-bisphosphate (PIP2) levels appear to control the balance between electrical and Ca2+ signaling. A major focus of our laboratory has been on the pathogenesis of Small Vessel Disease (SVD) of the brain, which is a major cause of stroke and dementia. Using a monogenic model of SVD (CADASIL) and our mechanistic insights into NVC, we discovered that SVD precipitates early defects in functional hyperemia, which we propose involve extracellular matrix changes and a loss of PIP2 activation of cEC Kir2.1 channels and suppression of TRPV4 channels. Importantly, we are able to rescue functional hyperemia in CADASIL through exogenous application of PIP2, suggesting a broad-spectrum approach for improving CBF control in disease. We have further found that hypertension, the major driver of sporadic SVDs, also leads to age-dependent deterioration of this major functional hyperemia mechanism. We propose to elucidate mechanisms for defective functional hyperemia in CADASIL (Aim 1) and hypertension (Aim 2), including common molecular intersections. A goal of this proposal is to create an integrated view of the impact of SVD on CBF regulation at molecular, biophysical, and computational-modeling levels by examining their operation in increasingly complex segments of the brain vasculature ex vivo, in vivo, and in silico.