ORAI Ca2+ channels and STIM1 drive capillary-to-arteriole communication in neurovascular coupling
Neurovascular coupling (NVC), which is initiated by the brain’s dense capillary network, matches blood flow to neuronal activity. We found that ORAI1 channels and their regulator STIM1, the main drivers of store-operated Ca2+ entry, were essential for communication from capillaries, which detect neuronal metabolic need, to upstream arterioles, which dilate to increase regional flow.
Endothelial cell–specific knockout of either Stim1 or Orai1 disrupted capillary Ca2+ signals, impaired sustained capillary-driven arteriole dilation, and reduced increases in blood flow in the somatosensory cortex evoked by whisker stimulation, indicating that ORAI1 and STIM1 sustain cerebral blood flow during prolonged neuronal stimulation. Moreover, mice with endothelial cell–specific deficiency of Stim1 or Orai1 showed cognitive impairment, whereas mice with endothelial cell–specific deficiency of Orai3 showed anxiety-like behaviors.
These in vivo results link impaired capillary-to-arteriole signaling to isoform-specific behavioral aberrations. These findings demonstrate that intravascular communication mediated by ORAI channels and STIM1 is fundamental for NVC and brain health.
EDITORS SUMMARY
Neurovascular coupling matches neuronal activity to blood flow from upstream arterioles into capillary beds. Lavanderos et al. found that Ca2+ signaling mediated by ORAI1 or ORAI3 channels and the Ca2+ sensor STIM1 in capillary endothelial cells was required for sustained arteriole dilation and cerebral perfusion during prolonged neuronal activity (see also the Focus by Dabertrand). In addition, deficiencies in these proteins in endothelial cells induced cognitive deficits reminiscent of early-stage vascular dementia or resulted in anxiety-like behaviors. Thus, ORAI channels and STIM1 in capillary endothelial cells reinforce vasodilatory signaling and support specific neurobehavioral functions.
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Boris Lavanderos; Alfredo Sanchez-Solano; Wanchun Zhu; Pratish Thakore; Evan Yamasaki; Yilin Chen; Yumei Feng Earley; Mohamed Trebak; Scott Earley
Neurovascular coupling (NVC), which is initiated by the brain’s dense capillary network, matches blood flow to neuronal activity. We found that ORAI1 channels and their regulator STIM1, the main drivers of store-operated Ca2+ entry, were essential for communication from capillaries, which detect neuronal metabolic need, to upstream arterioles, which dilate to increase regional flow.
Endothelial cell–specific knockout of either Stim1 or Orai1 disrupted capillary Ca2+ signals, impaired sustained capillary-driven arteriole dilation, and reduced increases in blood flow in the somatosensory cortex evoked by whisker stimulation, indicating that ORAI1 and STIM1 sustain cerebral blood flow during prolonged neuronal stimulation. Moreover, mice with endothelial cell–specific deficiency of Stim1 or Orai1 showed cognitive impairment, whereas mice with endothelial cell–specific deficiency of Orai3 showed anxiety-like behaviors.
These in vivo results link impaired capillary-to-arteriole signaling to isoform-specific behavioral aberrations. These findings demonstrate that intravascular communication mediated by ORAI channels and STIM1 is fundamental for NVC and brain health.
EDITORS SUMMARY
Neurovascular coupling matches neuronal activity to blood flow from upstream arterioles into capillary beds. Lavanderos et al. found that Ca2+ signaling mediated by ORAI1 or ORAI3 channels and the Ca2+ sensor STIM1 in capillary endothelial cells was required for sustained arteriole dilation and cerebral perfusion during prolonged neuronal activity (see also the Focus by Dabertrand). In addition, deficiencies in these proteins in endothelial cells induced cognitive deficits reminiscent of early-stage vascular dementia or resulted in anxiety-like behaviors. Thus, ORAI channels and STIM1 in capillary endothelial cells reinforce vasodilatory signaling and support specific neurobehavioral functions.
Web | DOI | PDF | Science Signaling | Paywall