Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone

Abstract

The brain possesses two intricate mechanisms that fulfill its continuous metabolic needs: cerebral autoregulation, which ensures constant cerebral blood flow over a wide range of arterial pressures and functional hyperemia, which ensures rapid delivery of oxygen and glucose to active neurons. Over the past decade, a number of important studies have identified astrocytes as key intermediaries in neurovascular coupling (NVC), the mechanism by which active neurons signal blood vessels to change their diameter. Activity-dependent increases in astrocytic Ca(2+) activity are thought to contribute to the release of vasoactive substances that facilitate arteriole vasodilation. A number of vasoactive signals have been identified and their role on vessel caliber assessed both in vitro and in vivo. In this review, we discuss mechanisms implicating astrocytes in NVC-mediated vascular responses, limitations encountered as a result of the challenges in maintaining all the constituents of the neurovascular unit intact and deliberate current controversial findings disputing a main role for astrocytes in NVC. Finally, we briefly discuss the potential role of pericytes and microglia in NVC-mediated processes.

Keywords: astrocyte; calcium; cerebral blood flow; myogenic tone; neurovascular coupling.

Figure 1

Representative illustration of the constituents of the neurovascular unit (NVU) from the capillary level to upstream pial arterioles. The diagram illustrates various control points across the cerebrovascular tree, involved in the integration of information that results in the coordinated delivery of oxygen and glucose to the brain under basal conditions and in response to increased metabolic demands. A simplified illustration of these control points, represented as levels 1–3, is shown in Fig 1. At the capillary level (level 1), the main constituents of the NVU include: endothelial cells, pericytes, astrocytes and neurons; level 1 represents the initiation site for neurovascular coupling-mediated responses. Of note, the endothelium continues throughout all levels (1–3). At level 2, the main constituents of the NVU include: a single layer of vascular smooth muscle cells (VSMCs) making up parenchymal arterioles, pericytes (not illustrated) and processes from both astrocytes and neurons. At level 3, the endothelium is surrounded by multiple layers of VSMCs making up pial arterioles, specialized astrocyte processes making up the glia limitans, and perivascular nerve endings originating from peripheral ganglia.

Figure 2

Hypothetical working model for the significance of astrocyte-mediated vasoconstriction. 1) Under resting conditions, basal vascular tone is set by the myogenic properties of the vascular smooth muscle cells (VSMCs) as well as a tonic vasoconstrictor influence from astrocytes (e.g. 20-HETE). 2) Increased neuronal activity (graded circles) causes the release of vasodilatory signals from both neurons and astrocytes resulting in a localized vasodilation, which rapidly overrides the myogenic constriction of the VSMC. 3) The rise in flow and pressure in distant arterioles however, favors vasoconstriction as the action of vasodilatory signals is now significantly diminished. We propose that the action of these opposing forces (vasodilation vs. vasoconstriction) contributes to the center surround phenomenon observed during functional hyperemia.