Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca(2+) signaling

Abstract

Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca(2+) signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca(2+) signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30) and channels formed by pannexins (Panx-1). The neuronal activity-initiated Ca(2+) waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca(2+) entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO) can activate connexin hemichannel by S-nitrosylation and the Ca(2+)-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca(2+) signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca(2+) influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca(2+) signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in this process.

Keywords: TRPV4 channels; cerebral arterioles; cerebral blood flow; connexins; endothelial nitric oxide synthase; gap junctions; neuronal nitric oxide synthase; pannexins.

Figure 1

Astrocyte-mediated signaling mechanisms involved in the control of neurovascular coupling. Neurotransmitters released during an increase in neuronal activity can exit the synaptic cleft and activate receptors on astrocyte processes. The stimulation of astrocyte receptors initiates an inositol 1, 4, 5-triphosphate (IP₃) receptor (IP₃R)-mediated Ca²⁺ signal that is propagated through the astrocytic processes into the endfeet and activates the phospholipase A₂ (PLA₂)–arachidonic acid (AA) pathway and large conductance Ca²⁺-activated K⁺ channels (BK_Ca). In turn, the activation PLA₂–AA pathway leads to cytochrome P450 epoxygenase (P450)-mediated epoxyeicosatrienoic acids (EETs) production and cyclooxygenase (COX)-dependent prostaglandin E₂ (PGE₂) formation. Consequently, EETs and PGE₂ release and BK_Ca channel opening evoke the vasodilation of parenchymal arterioles. The astrocyte-mediated vasodilator signal may be coordinated by the propagation of an inter-astrocyte Ca²⁺ signal via ATP release-mediated purinergic receptor (P₂) stimulation or directly by gap junction communication (GJ). ATP may be released by either Cx30- or Cx43-based hemichannels or pannexin-1 (Panx-1)-formed channels. The hydrolysis of ATP to adenosine (ADO) by ecto-ATPases may also contribute to enhance and coordinate the Ca²⁺ signal through A_2B receptor activation on astrocytes. ADO formation from Cx43 hemichannel-driven ATP release at the endfeet may participate in the vasodilator response by the stimulation of A_2A receptors on vascular smooth muscle cells (SMC) of parenchymal arterioles. The astrocytic Ca²⁺ signal may also activates nitric oxide (NO) production by both Ca²⁺-dependent constitutive NO synthases (cNOS), eNOS and nNOS, which may play an important role in the regulation of neurovascular coupling by the activation of Cx43 hemichannels and BK_Ca channels. It is noteworthy that Cx43 hemichannel opening may contribute to the Ca²⁺ signal by providing a pathway for Ca²⁺ influx and, in addition, may participate in the astrocytic vasodilator mechanisms by allowing the efficient release of PGE₂ and NO.