Bidirectional Control of Blood Flow by Astrocytes: A Role for Tissue Oxygen and Other Metabolic Factors

Abstract

Altering cerebral blood flow through the control of cerebral vessel diameter is critical so that the delivery of molecules important for proper brain functioning is matched to the activity level of neurons. Although the close relationship of brain glia known as astrocytes with cerebral blood vessels has long been recognized, it is only recently that these cells have been demonstrated to translate information on the activity level and energy demands of neurons to the vasculature. In particular, astrocytes respond to elevations in extracellular glutamate as a consequence of synaptic transmission through the activation of group 1 metabotropic glutamate receptors. These Gq-protein coupled receptors elevate intracellular calcium via IP3 signaling. A close examination of astrocyte endfeet calcium signals has been shown to cause either vasoconstriction or vasodilation. Common to both vasomotor responses is the generation of arachidonic acid in astrocytes by calcium sensitive phospholipase A2. Vasoconstriction ensues from the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid, while vasodilation ensues from the production of epoxyeicosatrienoic acids or prostaglandins. Factors that determine whether constrictor or dilatory pathways predominate include brain oxygen, lactate, adenosine as well as nitric oxide. Changing the oxygen level itself leads to many downstream changes that facilitate the switch from vasoconstriction at high oxygen to vasodilation at low oxygen. These findings highlight the importance of astrocytes as sensors of neural activity and metabolism to coordinate the delivery of essential nutrients via the blood to the working cells.

Selected aspects of retinal signaling and energy metabolism and its perspective as a cerebral surrogate model

“…For vasoconstriction, arachidonic acid is converted to 20-hydroxy eicosatetraenoic acid, and for vasodilatation, it is converted to epoxyeicosa trienoic acid or prostaglandins. Several factors determine the direction of action, including brain oxygen, lactate, adenosine as well as nitric oxide [38].…”

“…However, recent studies have shown that astrocytes are critical players in the regulation of cerebral blood vessel diameter for the purpose of adapted metabolism [37]. Astrocytes may act as sensors of neuronal activity and metabolism to coordinate the transport and delivery of nutrients and oxygen via the blood to metabolically active cells [38]. They are able to act bidirectional, causing either vasoconstriction or vasodilatation.…”

“…For vasoconstriction, arachidonic acid is converted to 20-hydroxy eicosatetraenoic acid, and for vasodilatation, it is converted to epoxyeicosa trienoic acid or prostaglandins. Several factors determine the direction of action, including brain oxygen, lactate, adenosine as well as nitric oxide [38].Within the neurovascular unit (neurons -astrocytesparenchymal arterioles), the neurovascular coupling adopts the local blood flow to the current neuronal activity. Under normal conditions, parenchymal arterioles may dilate and constrict according to metabolic demand in normophysiologic control compartments in the brain.…”

CrossTalk opposing view: the hypoxic ventilatory response does not include a central, excitatory hypoxia sensing component

“…A crucial role of astrocytes is sensing (and adapting) neural activity and metabolism, and translating this also into an adaptation of local vasomotor activity to defend the supply of oxygen and nutrients (Gordon et al . ; Mukandala et al . ).…”

“…In the event of local brain hypoxia or ischaemia, an increase in ventilation would be counterproductive: the resulting fall in P aCO2 would cause vasoconstriction and thus impede blood flow to the affected areas and other brain regions. A crucial role of astrocytes is sensing (and adapting) neural activity and metabolism, and translating this also into an adaptation of local vasomotor activity to defend the supply of oxygen and nutrients (Gordon et al 2016;Mukandala et al 2016). That O 2 sensitivity is a general property of astrocytes, rather than a distinctive feature of those located in the ventral medullary surface may suggest that although the latter are located in close association with the RTN, their primary role is to guard the supply of oxygen and nutrients by other means than by stimulating ventilation.…”