Vascular endothelial growth factor increases the function of calcium‐impermeable AMPA receptor GluA2 subunit in astrocytes via activation of protein kinase C signaling pathway

Abstract

Astrocytic calcium signaling plays pivotal roles in the maintenance of neural functions and neurovascular coupling in the brain. Vascular endothelial growth factor (VEGF), an original biological substance of vessels, regulates the movement of calcium and potassium ions across neuronal membrane. In this study, we investigated whether and how VEGF regulates glutamate‐induced calcium influx in astrocytes. We used cultured astrocytes combined with living cell imaging to detect the calcium influx induced by glutamate. We found that VEGF quickly inhibited the glutamate/hypoxia‐induced calcium influx, which was blocked by an AMPA receptor antagonist CNQX, but not D‐AP5 or UBP310, NMDA and kainate receptor antagonist, respectively. VEGF increased phosphorylation of PKCα and AMPA receptor subunit GluA2 in astrocytes, and these effects were diminished by SU1498 or calphostin C, a PKC inhibitor. With the pHluorin assay, we observed that VEGF significantly increased membrane insertion and expression of GluA2, but not GluA1, in astrocytes. Moreover, siRNA‐produced knockdown of GluA2 expression in astrocytes reversed the inhibitory effect of VEGF on glutamate‐induced calcium influx. Together, our results suggest that VEGF reduces glutamate‐induced calcium influx in astrocytes via enhancing PKCα‐mediated GluA2 phosphorylation, which in turn promotes the membrane insertion and expression of GluA2 and causes AMPA receptors to switch from calcium‐permeable to calcium‐impermeable receptors, thereby inhibiting astrocytic calcium influx. The present study reveals that excitatory neurotransmitter glutamate‐mediated astrocytic calcium influx can be regulated by vascular biological factor via activation of AMPA receptor GluA2 subunit and uncovers a novel coupling mechanism between astrocytes and endothelial cells within the neurovascular unit.

Extracellular Calcium Influx Pathways in Astrocyte Calcium Microdomain Physiology

“…However, quisqualate is not an iGluR-specific agonist and can activate metabotropic glutamate receptor I (mGluR I), which may have contributed to the mixed findings that QA-evoked Ca 2+ responses have an internal Ca 2+ store component [114,115,122]. Application of more specific agonists, such as AMPA, confirmed the presence of functional AMPARs on cultured hippocampal, cortical, and cerebellar astrocytes [122,123] as well as astrocytes in isolated optic nerve [124]. Third, astrocytes were cultured from different brain regions including the cortex, cerebellum, and hippocampus in these studies.…”

Acute Effects of High-Intensity Aerobic Exercise on Motor Cortical Excitability and Inhibition in Sedentary Adults

“…In addition to BDNF, other important neurotrophic factors for promoting neuroplasticity include nerve growth factor (NGF), which plays a role in the survival, growth, and differentiation of peripheral and central neurons ( Hall et al, 2018 ), glial cell line-derived neurotrophic factor (GDNF), also known for its role in neuronal survival in the central and peripheral nervous system and promotes recovery of damaged axons at the neuromuscular junction ( Cortés et al, 2017 ). Vascular endothelial growth factor (VEGF) promotes the growth of blood vasculature and can therefore increase neurovascular coupling ( Kou et al, 2019 ) and finally, insulin-like growth factor 1 (IGF-1) promotes anabolic growth in nearly all bodily tissues ( Wrigley et al, 2017 ). BDNF in particular is known to acutely enhance glutamatergic and reduce gamma aminobutyric acid (GABA)ergic synaptic transmission, thereby altering the excitation/inhibition balance in the brain by increasing the concentration of glutamate and reducing GABA concentrations ( Gottmann et al, 2009 ; Park and Poo, 2013 ).…”

Vascular endothelial growth factor promotes transdifferentiation of astrocytes into neurons via activation of the MAPK/Erk‐Pax6 signal pathway

“…Cortical astrocytes were obtained from 1 day of newborn Sprague Dawley rats (Kou et al, 2019). The cerebral cortex was dissected free of hippocampus and striatum, minced into small cubes of 1 mm 3 after removal of meninges and blood vessels.…”