Biology subjects

Tran, C. H. T.

Publications and source records attributed to Tran, C. H. T..

3 recordsLinked to original sources

bioRxiv2020

Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling

Blood flow regulation in the brain is dynamically regulated to meet the metabolic demands of active neuronal populations. Recent evidence has demonstrated that capillary endothelial cells are essential mediators of neurovascular coupling that sense neuronal activity and generate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles. Here, we tested the hypothesis that transient receptor potential ankyrin 1 (TRPA1) channels in capillary endothelial cells are significant contributors to functional hyperemic responses that underlie neurovascular coupling in the brain. Using an integrative ex vivo and in vivo approach, we demonstrate the functional presence of TRPA1 channels in brain capillary endothelial cells, and show that activation of these channels within the capillary bed, including the post-arteriole transitional region covered by ensheathing mural cells, initiates a retrograde signal that dilates upstream parenchymal arterioles. Notably, this signaling exhibits a unique biphasic mode of propagation that begins within the capillary network as a short-range, Ca2+ signal dependent on endothelial pannexin-1 channel/purinergic P2X receptor communication pathway and then is converted to a rapid, inward-rectifying K+ channel-mediated electrical signal in the post-arteriole transitional region that propagates upstream to parenchymal arterioles. Two-photon laser-scanning microscopy further demonstrated that conductive vasodilation occurs in vivo, and that TRPA1 is necessary for functional hyperemia within the somatosensory cortex of mice. Together, these data establish a role for endothelial TRPA1 channels as sensors of neuronal activity and show that they respond accordingly by initiating a vasodilatory response that redirects blood to regions of metabolic demand.

neuroscience↗

bioRxiv2019

Seizures cause sustained microvascular constriction associated with astrocytic and vascular smooth muscle Ca2+ recruitment

Previously we showed that seizures result in a severe hypoperfusion/hypoxic attack that results in postictal memory and behavioral impairments (Farrell et al., 2016). However, neither postictal changes in microvasculature nor Ca2+ changes in key cell-types controlling blood perfusion have been visualized in vivo, leaving essential components of the underlying cellular mechanisms unclear. Here we use two-photon microvascular and Ca2+ imaging in awake mice to show that seizures result in a robust vasoconstriction of cortical penetrating arterioles, which temporally mirrors the prolonged postictal hypoxia. The vascular effect was dependent on cyclooxygenase-2, as pre-treatment with ibuprofen prevented postictal vasoconstriction. Seizures caused a rapid elevation in astrocyte endfoot Ca2+ that was confined to the seizure period. Vascular smooth muscle cells displayed a significant increase in Ca2+ both during and following seizures, lasting up to 75 minutes. The temporal activities of two cell-types within the neurovascular unit lead to seizure-induced hypoxia.\n\nHighlightsO_LISeizures lead to equivalent levels of postictal hypoxia in both male and female mice\nC_LIO_LICalcium elevation in astrocyte endfeet is confined to the seizure\nC_LIO_LIPostictal vasoconstriction in awake mice is mediated by cyclooxygenase-2\nC_LIO_LICalcium elevation in vascular smooth muscle cells is enduring and correlates with vasoconstriction.\nC_LI

neuroscience↗

bioRxiv2019

Intercellular Conduction Optimizes Arterial Network Function and Conserves Blood Flow Homeostasis during Cerebrovascular Challenges

Cerebral arterial networks match blood flow delivery with neural activity. Neurovascular response begins with a stimulus and a focal change in vessel diameter, which by themselves is inconsequential to blood flow magnitude, until they spread and alter the contractile status of neighboring arterial segments. We sought to define the mechanisms underlying integrated vascular behavior and considered the role of intercellular electrical signalling in this phenomenon. Electron microscopic and histochemical analysis revealed the structural coupling of cerebrovascular cells and the expression of gap junctional subunits at the cell interfaces, enabling intercellular signaling among vascular cells. Indeed, robust vasomotor conduction was detected in human and mice cerebral arteries after focal vessel stimulation; a response attributed to endothelial gap junctional communication, as its genetic alteration attenuated this behavior. Conducted responses was observed to ascend from the penetrating arterioles, influencing the contractile status of cortical surface vessels, in a simulated model of cerebral arterial network. Ascending responses recognised in vivo after whisker stimulation, were significantly attenuated in mice with altered endothelial gap junctional signalling confirming that gap junctional communication drives integrated vessel responses. The diminishment in vascular communication also impaired the critical ability of the cerebral vasculature to maintain blood flow homeostasis and hence tissue viability, after stroke. Our findings establish the integral role of intercellular electrical signalling in transcribing focal stimuli into coordinated changes in cerebrovascular contractile activity and expose, a hitherto unknown mechanism for flow regulation after stroke.\n\nSignificanceNeurovascular responses are viewed as a one step process whereby stimuli derived from neural cells focally diffuse to a neighboring vessel, altering its contractile state. While focal changes in tone can subtly tune flow distribution, they cant substantively change \"perfusion magnitude\" as vascular resistance is broadly distributed along the cerebral arterial tree. We report that nature overcomes this biophysical constraint by conducting electrical signals among coupled vascular cells, along vessels, and across branch points. Our quantitative exploration of intercellular conduction illustrates how network coordination optimizes blood flow delivery in support of brain function. Diminishing the ability of vascular cells to electrically communicate, mitigates the brains ability to regulate perfusion during functional hyperemia and after stroke, the latter advancing tissue injury.

neuroscience↗