Brain endothelial cell TRPA1 channels initiate neurovascular coupling

Abstract

Cerebral blood flow is dynamically regulated by neurovascular coupling to meet the dynamic metabolic demands of the brain. We hypothesized that TRPA1 channels in capillary endothelial cells are stimulated by neuronal activity and instigate a propagating retrograde signal that dilates upstream parenchymal arterioles to initiate functional hyperemia. We find that activation of TRPA1 in capillary beds and post-arteriole transitional segments with mural cell coverage initiates retrograde signals that dilate upstream arterioles. These signals exhibit a unique mode of biphasic propagation. Slow, short-range intercellular Ca2+ signals in the capillary network are converted to rapid electrical signals in transitional segments that propagate to and dilate upstream arterioles. We further demonstrate that TRPA1 is necessary for functional hyperemia and neurovascular coupling within the somatosensory cortex of mice in vivo. These data establish endothelial cell TRPA1 channels as neuronal activity sensors that initiate microvascular vasodilatory responses to redirect blood to regions of metabolic demand.

Transient Receptor Potential Channel Ankyrin 1: A Unique Regulator of Vascular Function

“…An analysis of the conduction kinetics of vasodilator signals revealed that the propagation velocity of vasodilatory signals was significantly slower following application of TRPA1 agonists onto capillaries compared with that following application of K + . A further comparison of different vascular segments confirmed these results, showing that signals initiated by TRPA1 channels propagate much more slowly through deeper regions of the capillary network than those initiated by K ir channel activation [ 110 ]. However, we also showed that, in the post-arteriole transitional segment—a mural cell-rich region that bridges deeper reaches of the capillary network with its feeding parenchymal arteriole [ 113 ]—signal propagation is rapid and comparable to that produced by activating K ir channels [ 108 , 110 ].…”

“…Using whole-cell patch-clamp electrophysiology, we determined that TRPA1 channels are present and functional on native brain capillary endothelial cells. In a series of ex vivo experiments utilizing a recently characterized isolated ex vivo microvascular preparation that allows for pressure myography studies of brain arteriole segments attached to their capillary branches [ 108 ], we found that direct application of the TRPA1 agonists AITC or 4-HNE onto distal capillary extremities elicited transient, reversible, and reproducible dilatation of the connected upstream parenchymal arteriole [ 110 ]. This response was diminished in preparations from Trpa1 -ecKO mice, or by superfusing the TRPA1 antagonist HC-030031 or severing the capillaries from their upstream arteriole in preparations from wild-type mice.…”

“…The physiological relevance of TRPA1 in brain capillaries was demonstrated by assessing functional hyperemia in the somatosensory cortex of mice in vivo using laser Doppler flowmetry [ 111 , 112 ]. Stimulating contralateral whiskers for 5 s produced a reproducible increase in blood flow that was significantly diminished by blocking TRPA1 with HC-030031 and was blunted in Trpa1 -ecKO mice [ 110 ]. In contrast, blood flow increases in response to short-duration (1 and 2 s) stimulation were unchanged in mice treated with HC-030031 and did not differ between wild-type and Trpa1 -ecKO mice [ 110 ].…”

“…Stimulating contralateral whiskers for 5 s produced a reproducible increase in blood flow that was significantly diminished by blocking TRPA1 with HC-030031 and was blunted in Trpa1 -ecKO mice [ 110 ]. In contrast, blood flow increases in response to short-duration (1 and 2 s) stimulation were unchanged in mice treated with HC-030031 and did not differ between wild-type and Trpa1 -ecKO mice [ 110 ]. Thus, it appears that endothelial cell TRPA1 channels are not involved in functional hyperemic responses to short-duration (<5 s) stimuli, but are vital for maintaining responses during more prolonged stimulation.…”

“…TRPA1 channels in brain capillary endothelial cells initiate a novel biphasic propagating vasodilator signal [ 110 ] ( Figure 5 ). An analysis of the conduction kinetics of vasodilator signals revealed that the propagation velocity of vasodilatory signals was significantly slower following application of TRPA1 agonists onto capillaries compared with that following application of K + .…”