Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca2+ 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 Ca2+ signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca2+ 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 Ca2+ waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca2+ 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 Ca2+-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca2+ signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca2+ 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 Ca2+ signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in this process.

Astroglial glutamate transporters coordinate excitatory signaling and brain energetics

“…This increase in blood flow provides the signal analyzed in functional MRI analyses (for review, see Hillman, 2014; Raichle and Mintun, 2006). The mechanisms underlying this neurovascular coupling have been the subject of intense scrutiny and several different signals have been implicated (for reviews, see Attwell et al, 2010; Figley and Stroman, 2011; Howarth, 2014; Iadecola and Nedergaard, 2007; Koehler et al, 2009; Munoz et al, 2015; Petzold and Murthy, 2011; Tran and Gordon, 2015). The signals and cells that mediate this response are likely different for arterioles and capillaries (Attwell et al, 2010; Hall et al, 2014).…”

Connexin channel and its role in diabetic retinopathy

“…On the other hand, controlled opening of hemichannels plays an important role in neurovascular coupling, a process to maintain brain function with proper blood flow. Based on experimental data, it is suggested that neurovascular coupling may activate nitric oxide production which leads to Ca 2+ influx through hemichannels leading to the propagation of the signal to end feet of astrocytes to enhance the neurovascular coupling as reviewed in (Munoz et al, 2015). Also, nitric oxide released by the astrocytic hemichannels at end feet may contribute to the vasodilation.…”

Glial Cell Contribution to Basal Vessel Diameter and Pressure-Initiated Vascular Responses in Rat Retina

“…During neurovascular coupling, vasoactive signals arising from activated neurons or astrocytes influence local vessel tone and thus regulate regional blood flow to match the energetic needs of neuronal function. 6–9 This regulatory process is thought to be a feed-forward signaling pathway, starting with increased neuronal activity and resulting in changes in arteriole diameter. 10 It is known that triggering astrocyte calcium transients results in vasoconstriction of neighboring arterioles.…”