Astrocyte regulation of blood flow in the brain

Abstract

Neuronal activity results in increased blood flow in the brain, a response named functional hyperemia. Astrocytes play an important role in mediating this response. Neurotransmitters released from active neurons evoke Ca(2+) increases in astrocytes, leading to the release of vasoactive metabolites of arachidonic acid from astrocyte endfeet onto blood vessels. Synthesis of prostaglandin E2 (PGE2) and epoxyeicosatrienoic acids (EETs) dilate blood vessels, whereas 20-hydroxyeicosatetraenoic acid (20-HETE) constricts vessels. The release of K(+) from astrocyte endfeet may also contribute to vasodilation. Oxygen modulates astrocyte regulation of blood flow. Under normoxic conditions, astrocytic Ca(2+) signaling results in vasodilation, whereas under hyperoxic conditions, vasoconstriction is favored. Astrocytes also contribute to the generation of vascular tone. Tonic release of both 20-HETE and ATP from astrocytes constricts vascular smooth muscle cells, generating vessel tone. Under pathological conditions, including Alzheimer's disease and diabetic retinopathy, disruption of normal astrocyte physiology can compromise the regulation of blood flow.

Figure 1.

Drawing of brain astrocytes by Santiago Ramón y Cajal. (A,B) Astrocytes, the darker cells in the drawing, contact both neurons, (C,D) the lighter cells, and (F) a blood vessel. As suggested by Ramón y Cajal, astrocytes are ideally situated to mediate signaling from neurons to blood vessels and to increase cerebral blood flow (CBF) in response to neuronal activity.

Figure 2.

Summary of signaling pathways that mediate neurovascular coupling in the brain. Synaptically released glutamate acts on N-methyl-d-aspartate receptors (NMDARs) in neurons to increase [Ca²⁺]_i, causing neuronal nitric oxide synthase (nNOS) to release nitric oxide (NO), which activates smooth muscle guanylate cyclase. Raised [Ca²⁺]_i may also (dashed line) generate arachidonic acid (AA) from phospholipase A₂ (PLA₂), which is converted to prostaglandins (PG) that dilate vessels. Glutamate also raises [Ca²⁺]_i in astrocytes by activating metabotropic glutamate receptors (mGluR), generating arachidonic acid, and three types of AA metabolites: prostaglandins and EETs in astrocytes, which dilate vessels, and 20-HETE in smooth muscle, which constricts vessels. An increase of [Ca²⁺]_i in astrocyte endfeet may also activate Ca²⁺-gated K⁺ channels (g_k(Ca), alternative abbreviation, BK), releasing K⁺, which dilates vessels. (From Attwell et al. 2010; reprinted, with permission, from the authors.)

Figure 3.

Summary of the modulation of arachidonic acid metabolite-mediated neurovascular coupling by tissue pO₂ and lactate. Intracellular Ca²⁺ transients activate PLA₂ to liberate arachidonic acid (AA) from plasma membrane lipids. In high pO₂, AA is converted to 20-HETE, which increases intracellular Ca²⁺ in smooth muscle cells, causing vasoconstriction (left side). Extracellular adenosine that can inhibit Ca²⁺ entry into smooth muscle cells is also lower in high tissue pO₂, further promoting vasoconstriction. In lower pO₂ (right side), the vasodilation pathway dominates and AA is converted to PGE2 by COX-1 and is released by diffusion. Extracellular PGE2 is cleared from the extracellular space by the prostaglandin transporter (PGT), which is expressed in astrocytes and neurons. When pO₂ decreases, glycolysis is enhanced and extracellular levels of lactate increase. Extracellular lactate attenuates PGE2 uptake by PGT leading to higher extracellular PGE2 and enhanced relaxation of smooth muscle tone and vasodilation. In addition, higher levels of extracellular adenosine reduces smooth muscle cell constriction via A_2A activation. (From Gordon et al. 2011; reprinted, with permission, from the authors.)

Figure 4.

Flicker-induced vasodilation of retinal blood vessels is depressed in diabetic retinopathy. (A) Flicker-induced vasodilation of primary arterioles and venules is depressed in patients with type 1 diabetes. (Panel A is from Pemp et al. 2009; reprinted, with permission, from the Association for Research in Vision and Ophthalmology © 2009.) B and C show that the depression of flicker-induced vasodilation in diabetic rats is reversed by the iNOS inhibitor aminoguanidine (AG). (B) Both acute AG administration (AG-IV) and chronic administration in drinking water (AG-H₂O) reverses the loss of flicker-induced vasodilation in diabetic animals in vivo. (C) Summary of results. (Panels B and C are from Mishra and Newman 2012; reprinted, with permission, from the authors and Frontiers in Neuroscience Creative Common attribution license.)