Ion channel networks in the control of cerebral blood flow

Abstract

One hundred and twenty five years ago, Roy and Sherrington made the seminal observation that neuronal stimulation evokes an increase in cerebral blood flow.1 Since this discovery, researchers have attempted to uncover how the cells of the neurovascular unit-neurons, astrocytes, vascular smooth muscle cells, vascular endothelial cells and pericytes-coordinate their activity to control this phenomenon. Recent work has revealed that ionic fluxes through a diverse array of ion channel species allow the cells of the neurovascular unit to engage in multicellular signaling processes that dictate local hemodynamics. In this review we center our discussion on two major themes: (1) the roles of ion channels in the dynamic modulation of parenchymal arteriole smooth muscle membrane potential, which is central to the control of arteriolar diameter and therefore must be harnessed to permit changes in downstream cerebral blood flow, and (2) the striking similarities in the ion channel complements employed in astrocytic endfeet and endothelial cells, enabling dual control of smooth muscle from either side of the blood-brain barrier. We conclude with a discussion of the emerging roles of pericyte and capillary endothelial cell ion channels in neurovascular coupling, which will provide fertile ground for future breakthroughs in the field.

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

“…These neural processes originate from interneurons or from subcortical and brainstem nuclei projecting to the cortex, such as the basal forebrain cholinergic nuclei, locus coeruleus, and raphe magnus (Cohen et al, 1996; Hamel, 2006; Iadecola, 1993). Endothelial cells extend protrusions through the basal lamina into SMC (myoendothelial projections) enriched with gap junctions (Dahl, 1973; Longden et al, 2016). As arterioles transition into cerebral capillaries (Figure 5), SMC are replaced by pericytes, mural cells embedded into the endothelial basement membrane, covering approximately 30% of the vascular surface, and occasionally extending “peg and socket” protrusions into endothelial cells (Armulik et al, 2011; Dahl, 1973; Damisah et al, 2017).…”

“…SMC constrict and relax in response to a wide variety of vasoactive agents and to conducted vasodilatatory stimuli originating from downstream vessels (see previous section). Another key physiological characteristic of SMC is their ability to constrict or relax in response to increases or decreases in intravascular pressure, a phenomenon termed myogenic response (Cipolla, 2010; Longden et al, 2016). Cerebral arteries, especially penetrating arterioles, have a strong propensity to generate myogenic tone, a property that is essential for cerebral blood vessels to keep CBF stable during changes in arterial pressure within a certain range (cerebrovascular autoregulation) (Koller and Toth, 2012).…”

Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states

“…Other mediators or modulators of the sensory-evoked NVC response have been identified [49], including astroglial large-conductance, calcium-operated (BK) and smooth muscle cell inward-rectifier (Kir) potassium channels [12,39,137,138], endothelial hyperpolarization and prostanoid-dependent dilation [13], and neurally derived NO [139].…”

Calcium and electrical signaling in arterial endothelial tubes: New insights into cellular physiology and cardiovascular function

“…The endothelium plays an integral role towards the production of hyperpolarization, vasodilation, and tissue perfusion (3, 6, 10, 66, 67) and thus, examination of its cellular properties in its native state is crucial. As an alternative to the study of single isolated ECs and/or cell culture, use of intact endothelial “tubes” (see Figure 1A) freshly isolated from hamster cremaster arterioles was first developed and published by the Jackson laboratory (68).…”