Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow

Abstract

Blood flow into the brain is dynamically regulated to satisfy the changing metabolic requirements of neurons, but how this is accomplished has remained unclear. Here, we demonstrate a central role for capillary endothelial cells in sensing neural activity and communicating it to upstream arterioles in the form of an electrical vasodilatory signal. We further demonstrate that this signal is initiated by extracellular potassium (K+)—a byproduct of neural activity—which activates capillary endothelial cell inward-rectifier K+ (KIR2.1) channels to produce a rapidly propagating retrograde hyperpolarization that causes upstream arteriolar dilation, increasing blood flow into the capillary bed. Our results establish brain capillaries as an active sensory web that converts changes in external K+ into rapid, ‘inside-out’ electrical signaling to direct blood flow to active brain regions.

Entrainment of Arteriole Vasomotor Fluctuations by Neural Activity Is a Basis of Blood-Oxygenation-Level-Dependent “Resting-State” Connectivity

“…Yet the observed spatial scale nominally corresponds to the ~2 mm electrotonic length along the endothelial cells that form the lumen of the vessel (Segal and Duling, 1989). We thus surmise that intrahemispheric coherence within the arteriole network is in part mediated by signaling along endothelial cells that form the lumen (Longden et al, 2017), in addition to neuronal interactions. This view is supported by disruption of the front of vasodilation by precise light-induced disruption of conducted dilation within the arteriole network (Chen et al, 2014).…”

“…A final unknown concerns the precise mechanism by which neurons drive the endothelial cells (Attwell and Iadecola, 2002; Cauli and Hamel, 2010). Likely candidates for prompt signaling to arterioles are prostaglandin release (Lacroix et al, 2015) and bursts of potassium in the perivascular space (Longden et al, 2017). These mechanisms are important on fundamental grounds (Kleinfeld et al, 2011) and as a means to further improve the interpretation of BOLD (Logothetis and Wandell, 2004).…”

The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

“…For example, in the auditory, visual and cerebellar cortex the vascular response does not faithfully match the activated area (Harrison et al, 2002; Iadecola et al, 1997; O’Herron et al, 2016), while in the olfactory bulb there is close overlap between the two (Chaigneau et al, 2003). Non-overlapping vascular and neuronal topology in neocortex (Blinder et al, 2013) and retrograde vasodilatation (discussed later in this review) are likely responsible for such lack of fidelity (Chen et al, 2014; Iadecola et al, 1997; Longden et al, 2017). Since hemodynamic signals are the most powerful tool at our disposal for functional brain mapping, their spatial alignment with neural activity is becoming increasingly relevant as the resolution of fMRI increases.…”

“…Although much less in know about the mechanisms of retrograde vasodilatation in the cerebral vasculature, a recent study implicates endothelial K IR channels, rather than K Ca , in the mechanisms of the fast component. Enriched with K IR channels, but not K Ca channels, capillary cerebral endothelial cells are highly sensitive to K + generated during neural activity, either from the abutting astrocytic end-feet or diffusion form nearby synapses (Longden et al, 2017). Owing to a unique capillary-parenchymal arteriole preparation, this study showed that micropipette application of 6–10mM K + to capillaries generated a robust hyperpolarization in endothelial cells, transmitted retrogradely to penetrating arterioles at an estimated speed of 2mm/sec, and leading to hyperpolarization and relaxation of SMC (Longden et al, 2017).…”

“…Enriched with K IR channels, but not K Ca channels, capillary cerebral endothelial cells are highly sensitive to K + generated during neural activity, either from the abutting astrocytic end-feet or diffusion form nearby synapses (Longden et al, 2017). Owing to a unique capillary-parenchymal arteriole preparation, this study showed that micropipette application of 6–10mM K + to capillaries generated a robust hyperpolarization in endothelial cells, transmitted retrogradely to penetrating arterioles at an estimated speed of 2mm/sec, and leading to hyperpolarization and relaxation of SMC (Longden et al, 2017). K + application did not induce capillary dilatation, suggesting that the capillary was the K + sensor and the upstream penetrating arteriole the effector of the vasodilation.…”