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Biological tissues are fed by arterial networks whose task is to set blood flow delivery in accordance with energetic demand. Coordinating vasomotor activity among hundreds of neighboring segments is an essential process, one dependent upon electrical information spreading among smooth muscle and endothelial cells. The "conducted vasomotor response" is a functional expression of electrical spread, and it is this process that lies at the heart of this critical review. Written in a narrative format, this review first highlights historical manuscripts and then characterizes the conducted response across a range of preparations. Trends are highlighted and used to guide subsequent sections, focused on cellular foundations, biophysical underpinnings, and regulation in health and disease. Key information has been tabulated; figures reinforce grounding concepts and reveal a framework within which theoretical and experimental work can be rationalized. This summative review highlights that despite 30 years of concerted experimentation, key aspects of the conducted response remain ill defined. Of note is the need to rationalize the regulation and deterioration of conduction in pathobiological settings. New quantitative tools, along with transgenic technology, are discussed as a means of propelling this investigative field forward.

The arterial myogenic response to intraluminal pressure elicits constriction to maintain tissue perfusion. Smooth muscle [Ca 2+ ] is a key determinant of constriction, tied to L-type (Ca V 1.2) Ca 2+ channels. While important, other Ca 2+ channels, particularly T-type could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca 2+ channel (Ca V 3.1) using C57BL/6 wild type and Ca V 3.1 -/- mice. Patch-clamp electrophysiology, pressure myography, blood pressure and Ca 2+ imaging defined the Ca V 3.1 -/- phenotype relative to C57BL/6. Ca V 3.1 -/- mice had absent Ca V 3.1 expression and whole-cell current, coinciding with lower blood pressure and reduced mesenteric artery myogenic tone, particularly at lower pressures (20-60 mmHg) where membrane potential is hyperpolarized. This reduction coincided with diminished Ca 2+ wave generation, asynchronous events of Ca 2+ release from the sarcoplasmic reticulum, insensitive to L-type Ca 2+ channel blockade (Nifedipine, 0.3 µM). Proximity ligation assay (PLA) confirmed IP 3 R1/Ca V 3.1 close physical association. IP 3 R blockade (2-APB, 50 µM or xestospongin C, 3 µM) in nifedipine-treated C57BL/6 arteries rendered a Ca V 3.1 -/- contractile phenotype. Findings indicate that Ca 2+ influx through Ca V 3.1 contributes to myogenic tone at hyperpolarized voltages through Ca 2+ -induced Ca 2+ release tied to the sarcoplasmic reticulum. This study helps establish Ca V 3.1 as a potential therapeutic target to control blood pressure., (© 2023. The Author(s).)

Vascular smooth muscle contraction is intimately tied to membrane potential and the rise in intracellular Ca 2+ enabled by the opening of L-type Ca 2+ channels. While voltage is often viewed as the single critical factor gating these channels, research is starting to reveal a more intricate scenario whereby their function is markedly tuned. This emerging concept will be the focus of this three-part review, the first part articulating the mechanistic foundation of contractile development in vascular smooth muscle. Part two will extend this foundational knowledge, introducing readers to functional coupling and how neighboring L-type Ca 2+ channels work cooperatively through signaling protein complexes, to facilitate their open probability. The final aspect of this review will discuss the impact of L-type Ca 2+ channel trafficking, a process tied to cytoskeleton dynamics. Cumulatively, this brief manuscript provides new insight into how voltage, along with channel cooperativity and number, work in concert to tune Ca 2+ responses and smooth muscle contraction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mironova, Haghbin and Welsh.)

Cerebral blood flow is a finely tuned process dependent on coordinated changes in arterial tone. These changes are strongly tied to smooth muscle membrane potential and inwardly rectifying K + (K IR ) channels are thought to be a key determinant. To elucidate the role of K IR 2.1 in cerebral arterial tone development, this study examined the electrical and functional properties of cells, vessels and living tissue from tamoxifen-induced smooth muscle cell (SMC)-specific K IR 2.1 knockout mice. Patch-clamp electrophysiology revealed a robust Ba 2+ -sensitive inwardly rectifying K + current in cerebral arterial myocytes irrespective of K IR 2.1 knockout. Immunolabeling clarified that K IR 2.1 expression was low in SMCs while K IR 2.2 labeling was remarkably abundant at the membrane. In alignment with these observations, pressure myography revealed that the myogenic response and K + -induced dilation were intact in cerebral arteries post knockout. At the whole organ level, this translated to a maintenance of brain perfusion in SMC K IR 2.1 -/- mice, as assessed with arterial spin-labeling MRI. We confirmed these findings in superior epigastric arteries and implicated K IR 2.2 as more functionally relevant in SMCs. Together, these results suggest that subunits other than K IR 2.1 play a significant role in setting native current in SMCs and driving arterial tone.

Objective: The myogenic response sets the foundation for blood flow control. Recent findings suggest a role for G protein-coupled receptors (GPCR) and signaling pathways tied to the generation of reactive oxygen species (ROS). In this regard, this study ascertained the impact of NADPH oxidase (Nox) on myogenic tone in rat cerebral resistance arteries., Methods: The study employed real-time qPCR (RT-qPCR), pressure myography, and immunohistochemistry., Results: G q blockade abolished myogenic tone in rat cerebral arteries, linking GPCR to mechanosensation. Subsequent work revealed that general (TEMPOL) and mitochondrial specific (MitoTEMPO) ROS scavengers had little impact on myogenic tone, whereas apocynin, a broad spectrum Nox inhibitor, initiated transient dilation. RT-qPCR revealed Nox1 and Nox2 mRNA expression in smooth muscle cells. Pressure myography defined Nox1 rather than Nox2 is facilitating myogenic tone. We rationalized that Nox1-generated ROS was initiating this response by impairing the ability of the Ca V 3.2 channel to elicit negative feedback via BK Ca . This hypothesis was confirmed in functional experiments. The proximity ligation assay further revealed that Nox1 and Ca V 3.2 colocalize within 40 nm of one another., Conclusions: Our data highlight that vascular pressurization augments Nox1 activity and ensuing ROS production facilitates myogenic tone by limiting Ca 2+ influx via Ca V 3.2., (© 2022 John Wiley & Sons Ltd.)

In this study, we investigated the effects of NAD(P)H oxidase (NOX) inhibitor VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) on the histamine-induced elevation of free cytoplasmic calcium concentration ([Ca 2+ ] i ) and the secretion of von Willebrand factor (vWF) in human umbilical vein endothelial cells (HUVECs) and on relaxation of rat aorta in response to histamine. At 10 μM concentration, VAS2870 suppressed the [Ca 2+ ] i rise induced by histamine. Inhibition was not competitive, with IC50 3.64 and 3.22 μM at 1 and 100 μM concentrations of histamine, respectively. There was no inhibition of [Ca 2+ ] i elevation by VAS2870 in HUVECs in response to the agonist of type 1 protease-activated receptor SFLLRN. VAS2870 attenuated histamine-induced secretion of vWF and did not inhibit basal secretion. VAS2870 did not change the degree of histamine-induced relaxation of rat aortic rings constricted by norepinephrine. We suggest that NOX inhibitors might be used as a tool for preventing thrombosis induced by histamine release from mast cells without affecting vasorelaxation.

Hydrogen peroxide, formed in the endothelium, acts as a factor contributing to the relaxation of blood vessels. The reason for this vasodilatory effect could be modulation by H 2 O 2 of calcium metabolism, since mobilization of calcium ions in endothelial cells is a trigger of endothelium-dependent relaxation. The aim of this work was to investigate the influence of H 2 O 2 on the effects of Ca 2+ -mobilizing agonists in human umbilical vein endothelial cells (HUVEC). We have found that H 2 O 2 in concentration range 10-100  μ M increases the rise of [Ca 2+ ] i induced by 5-hydroxytryptamine (5-HT) and carbachol and does not affect the calcium signals of ATP, agonist of type 1 protease-activated receptor SFLLRN, histamine and bradykinin. Using specific agonists of 5-HT1B and 5-HT2B receptors CGS12066B and BW723C86, we have demonstrated that H 2 O 2 potentiates the effects mediated by these types of 5-HT receptors. Potentiation of the effect of BW723C86 can be produced by the induction of endogenous oxidative stress in HUVEC. We have shown that the activation of 5-HT2B receptor by BW723C86 causes production of reactive oxygen species (ROS). Inhibitor of NADPH oxidases VAS2870 suppressed formation of ROS and partially inhibited [Ca 2+ ] i rise induced by BW723C86. Thus, it can be assumed that vasorelaxation induced by endogenous H 2 O 2 in endothelial cells partially occurs due to the potentiation of the agonist-induced calcium signaling.

Hydrogen peroxide at concentrations below cytotoxic ones causes an increase in the cytoplasmic calcium concentration in human umbilical vein endothelial cells as a result of calcium release from intracellular stores. Two-pore calcium channel blocker trans-NED19 partially suppresses the increase in the level of calcium ions in the cells in response to the addition of hydrogen peroxide. The staining of endothelial cells with the fluorescent stereoisomer cis-NED19 and LysoTracker confirmed the localization of two-pore calcium channels in lysosomes and endolysosomal vesicles.

In blood vessels, serotonin 5-HT2B receptors mainly mediate relaxation, although their activation by the selective agonist BW723C86 is known to exert contraction of aorta in deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-l-arginine (l-NAME) hypertensive rats [Russel et al., 2002; Banes et al., 2003] and in mice with type 2 diabetes [Nelson et al., 2012]. The unmasking effect on vasoconstriction can be caused by a shift in the balance of tyrosine phosphorylation in smooth muscle cells (SMC) due to oxidative stress induced inhibition of protein tyrosine phosphatases (PTP). We have demonstrated that BW723C86 which does not cause contraction of rat aorta and mesenteric artery rings, evoked a vasoconstrictor effect in the presence of PTP inhibitors sodium orthovanadate (Na 3 VO 4 ) or BVT948. BW723C86 induced a weak rise of [Ca 2+ ] i in the SMC isolated from rat aorta; however, after pre-incubation with Na 3 VO 4 the response to BW723C86 increased more than 5-fold. This effect was diminished by protein tyrosine kinase (PTK) inhibitor genistein, inhibitor of Src-family kinases PP2, inhibitor of NADPH-oxidase VAS2870 and completely suppressed by N-acetylcysteine and 5-HT2B receptor antagonist RS127445. Using fluorescent probe DCFH-DA we have shown that Na 3 VO 4 induces oxidative stress in SMC. In the presence of Na 3 VO 4 BW723C86 considerably increased formation of reactive oxygen species while alone had no appreciable effect on DCFH oxidation. We suggest that oxidative stress causes inhibition of PTP and unmasking of 5-HT2B receptors functional activity., (Copyright © 2016 Elsevier Inc. All rights reserved.)