Kir Mediates Regenerative and Directional Conduction of Hyperpolarization in Brain Capillaries: Importance for Neurovascular Coupling

IntroductionRapid increase in local blood perfusion in response to elevated neuronal activity, a process referred to as neurovascular coupling (NVC), is crucial to the functioning and survival of neurons. Impairment of NVC is associated to a variety of neurological disorders including Alzheimer's disease, stroke, and vascular dementia [1]. Data by Longden et al. [2] suggest an active role of capillary endothelial cells (Cap‐ECs) in NVC. Inwardly rectifying potassium channels (Kir) enable capillaries to a) sense K+ release by nearby active neurons and b) amplify and conduct the resulting hyperpolarization to upstream feeding arterioles to increase cerebral blood flow (CBF) locally. Data by Twynstra et al. [3] in skeletal muscle microvasculature have also shown that propagating vasodilation becomes more specific in its direction as the branch order increases and that preferential conduction of vasodilatory signals in the upstream direction is possible through a yet unidentified mechanism. In this study, we use a mathematical model of a capillary network and its feeding parenchymal arteriole (PA), to examine the biophysical determinants that allow capillaries to sense modest elevations of K+ and transmit vasodilatory signals. We hypothesize that capillary level NVC is feasible through mechanisms that promote regenerative signal propagation in a preferentially upstream direction in the microvascular network.MethodsDetailed mathematical models of Cap‐ECs and PA ECs and smooth muscle cells (SMCs) are constructed. The models entail the dynamics of major ionic channels and intracellular components and predict membrane potential (Vm) and Ca2+ dynamics. Cap‐ECs are coupled through gap junctions to form a branched capillary network that is connected to a feeding PA (Fig 1A). Both local and distal hyperpolarizations are examined in response to K+ stimuli at different locations along the capillary network.ResultsSimulations predict a critical level of Kir density for generating local and conducted K+‐induced hyperpolarization in a series of connected Cap‐ECs (Fig 1B). When Kir current is small relative to the total transmembrane current, a passive spread of hyperpolarization is predicted (Fig. 1B; GKir,max ≈ 0.1 nS). Conversely, when Kir is dominant, the local hyperpolarization is significantly larger and the vasodilatory signal is conducted along the endothelial layer without signal attenuation (Fig 1B; GKir,max ≈ 0.3 nS). Furthermore, simulations in a simplified capillary network (Fig 1C), show that increasing Kir density upstream of bifurcations, allows preferential upstream conduction of the hyperpolarizing signal.ConclusionModel simulations suggest that Kir channels can mediate preferential and regenerative propagation of vasodilatory signals upstream the vascular network. This allows brain capillaries to effectively transmit vasodilatory signaling to feeding arterioles, in response to neuronal activity, and regulate local CBF.Support or Funding InformationThis work was supported by NIH grants R01HL131181 (to MTN), R01HL136636 (to FD), 1R15HL121778‐01A1.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.