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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 Ca 2+ 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., Competing Interests: PT, MA, SA, AM, PP, EY, HP, BI, CT, SE No competing interests declared, (© 2021, Thakore et al.)

The article discusses the impact of hypertension on endothelial dysfunction and its role in regulating blood flow. It highlights the importance of KIR2.1 channels in promoting flow-induced vasodilation and the impairment of these channels in hypertensive arteries. The study by Do Couto et al. demonstrates that recovering KIR2.1 function could improve endothelial response to shear stress in hypertensive vessels, potentially leading to reduced blood pressure and hypertensive end-organ damage. Further research is needed to explore the mechanisms underlying KIR2.1 dysfunction in hypertension and its potential implications for vascular health. [Extracted from the article]

Aging is associated with cognitive decline via incompletely understood mechanisms. Cerebral microvascular dysfunction occurs in aging, particularly impaired endothelium-mediated dilation. Parenchymal arterioles are bottlenecks of cerebral microcirculation, and dysfunction causes a mismatch in nutrient demand and delivery, leaving neurons at risk. Extracellular nucleotides elicit parenchymal arteriole dilation by activating endothelial purinergic receptors (P2Y), leading to the opening of K+ channels, including inwardly rectifying K+ channels (Kir2). These channels amplify hyperpolarizing signals, resulting in dilation. However, it remains unknown if endothelial P2Y and Kir2 signaling are altered in brain parenchymal arterioles during aging. We hypothesized that aging impairs endothelial P2Y and Kir2 function in parenchymal arterioles. We observed reduced dilation to the purinergic agonist 2-methyl-S-ADP (1 μM) in arterioles from aged (>24 mo old) mice when compared with young (4-6 mo of age) despite similar hyperpolarization in endothelial cell tubes. No differences were observed in vasodilation or endothelial cell hyperpolarization to activation of small- and intermediate-conductance Ca2+-activated K+ channels (KCa2.3/KCa3.1) by NS309. Hyperpolarization to 15 mM [K+]e was smaller in aged than young mice, despite a paradoxically increased dilation in aged arterioles to 15 mM [K+]e that was unchanged by endothelium removal. Kir2 inhibition attenuated vasodilatory responses to 15 mM [K+]e and 1 #956;M 2-me-S-ADP in both young and aged arterioles. Furthermore, we observed a significant increase in myogenic tone in aged parenchymal arterioles, which was not enhanced by endothelium removal. We conclude that aging impairs endothelial Kir2 channel function in the cerebral microcirculation with possible compensation by smooth muscle cells. [ABSTRACT FROM AUTHOR]

Objective Chronic hypertension induces detrimental changes in the structure and function of surface cerebral arteries. Very little is known about PAs, which perfuse distinct neuronal populations in the cortex and may play a role in cerebrovascular disorders. We investigated the effect of DOCA-salt induced hypertension on endothelial function and artery structure in PAs and MCAs. Methods Uninephrectomized male Sprague-Dawley rats were implanted with a subcutaneous pellet containing DOCA (150 mg/kg b.w.) and drank salt water (1% NaCl and 0.2% KCl) for 4 weeks. Sham rats were uninephrectomized and drank tap water. Vasoreactivity and passive structure in the MCAs and the PAs were assessed by pressure myography. Results Both MCAs and PAs from DOCA-salt rats exhibited impaired endothelium-dependent dilation ( P<.05). In the PAs, addition of NO and COX inhibitors enhanced dilation in DOCA-salt rats ( P<.05), suggesting that dysfunctional NO and COX-dependent signaling could contribute to impaired endothelium-mediated dilation. MCAs from DOCA-salt rats exhibited inward remodeling ( P<.05). Conclusions Hypertension-induced MCA remodeling coupled with impaired endothelium-dependent dilation in both the MCAs and PAs may exacerbate the risk of cerebrovascular accidents and the associated morbidity and mortality. [ABSTRACT FROM AUTHOR]

Cerebral parenchymal arterioles (PA) regulate blood flow between pial arteries on the surface of the brain and the deeper microcirculation. Regulation of PA contractility differs from that of pial arteries and is not completely understood. Here, we investigated the hypothesis that the Ca2+ permeable vanilloid transient receptor potential (TRPV) channel TRPV3 can mediate endothelium-dependent dilation of cerebral PA. Using total internal reflection fluorescence microscopy (TIRFM), we found that carvacrol, a monoterpenoid compound derived from oregano, increased the frequency of unitary Ca2+ influx events through TRPV3 channels (TRPV3 sparklets) in endothelial cells from pial arteries and PAs. Carvacrol-induced TRPV3 sparklets were inhibited by the selective TRPV3 blocker isopentenyl pyrophosphate (IPP). TRPV3 sparklets have a greater unitary amplitude (ΔF/F0 = 0.20) than previously characterized TRPV4 (AF/F0 = 0.06) or TRPA1 (AF/F0 = 0.13) sparklets, suggesting that TRPV3-mediated Ca2+ influx could have a robust influence on cerebrovascular tone. In pressure myography experiments, carvacrol caused dilation of cerebral PA that was blocked by IPP. Carvacrol-induced dilation was nearly abolished by removal of the endothelium and block of intermediate (IK) and small-conductance Ca2+-activated K+ (SK) channels. Together, these data suggest that TRPV3 sparklets cause dilation of cerebral parenchymal arterioles by activating IK and SK channels in the endothelium. [ABSTRACT FROM AUTHOR]

Background Inflammation is involved in the pathogenesis of hypertension. Hypertensive animals have an increased number of perivascular macrophages in cerebral arteries. Macrophages might be involved in remodeling of the cerebral vasculature. We hypothesized that peripheral macrophage depletion would improve MCA structure and function in hypertensive rats. Methods For macrophage depletion, six-week-old stroke-prone spontaneously hypertensive rats ( SHRSP) were treated with CLOD, 10 mL/kg every three or four days, i.p., or vehicle ( PBS lipo). MCA structure and function were analyzed by pressure and wire myography. Results Blood pressure was not affected by CLOD. The number of perivascular CD163-positive cells per microscopic field was reduced in the brain of SHRSP+ CLOD. CLOD treatment caused an improvement in endothelium-dependent dilation after intralumenal perfusion of ADP and incubation with Ach. Inhibition of NO production blunted the Ach response, and endothelium-independent dilation was not altered. At an intralumenal pressure of 80 mmHg, MCA from SHRSP+ CLOD showed increased lumen diameter, decreased wall thickness, and wall-to-lumen ratio. Cross-sectional area of pial arterioles from SHRSP+ CLOD was higher than PBS lipo. Conclusions These results suggest that macrophage depletion attenuates MCA remodeling and improves MCA endothelial function in SHRSP. [ABSTRACT FROM AUTHOR]