Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury

Background and Purpose: Circadian rhythms influence the extent of brain injury following subarachnoid hemorrhage (SAH), but the mechanism is unknown. We hypothesized that cerebrovascular myogenic reactivity is rhythmic and explains the circadian variation in SAH-induced injury. Methods: SAH was modeled in mice with prechiasmatic blood injection. Inducible, smooth muscle cell–specific Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1) gene deletion (smooth muscle–specific Bmal1 1 knockout [sm-Bmal1 KO]) disrupted circadian rhythms within the cerebral microcirculation. Olfactory cerebral resistance arteries were functionally assessed by pressure myography in vitro; these functional assessments were related to polymerase chain reaction/Western blot data, brain histology (Fluoro-Jade/activated caspase-3), and neurobehavioral assessments (modified Garcia scores). Results: Cerebrovascular myogenic vasoconstriction is rhythmic, with a peak and trough at Zeitgeber times 23 and 11 (ZT23 and ZT11), respectively. Histological and neurobehavioral assessments demonstrate that higher injury levels occur when SAH is induced at ZT23, compared with ZT11. In sm-Bmal1 KO mice, myogenic reactivity is not rhythmic. Interestingly, myogenic tone is higher at ZT11 versus ZT23 in sm-Bmal1 KO mice; accordingly, SAH-induced injury in sm-Bmal1 KO mice is more severe when SAH is induced at ZT11 compared to ZT23. We examined several myogenic signaling components and found that CFTR (cystic fibrosis transmembrane conductance regulator) expression is rhythmic in cerebral arteries. Pharmacologically stabilizing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) eliminates the rhythmicity in myogenic reactivity and abolishes the circadian variation in SAH-induced neurological injury. Conclusions: Cerebrovascular myogenic reactivity is rhythmic. The level of myogenic tone at the time of SAH ictus is a key factor influencing the extent of injury. Circadian oscillations in cerebrovascular CFTR expression appear to underlie the cerebrovascular myogenic reactivity rhythm.

Calcium-Dependent Ion Channels and the Regulation of Arteriolar Myogenic Tone

Arterioles in the peripheral microcirculation regulate blood flow to and within tissues and organs, control capillary blood pressure and microvascular fluid exchange, govern peripheral vascular resistance, and contribute to the regulation of blood pressure. These important microvessels display pressure-dependent myogenic tone, the steady state level of contractile activity of vascular smooth muscle cells (VSMCs) that sets resting arteriolar internal diameter such that arterioles can both dilate and constrict to meet the blood flow and pressure needs of the tissues and organs that they perfuse. This perspective will focus on the Ca2+-dependent ion channels in the plasma and endoplasmic reticulum membranes of arteriolar VSMCs and endothelial cells (ECs) that regulate arteriolar tone. In VSMCs, Ca2+-dependent negative feedback regulation of myogenic tone is mediated by Ca2+-activated K+ (BKCa) channels and also Ca2+-dependent inactivation of voltage-gated Ca2+ channels (VGCC). Transient receptor potential subfamily M, member 4 channels (TRPM4); Ca2+-activated Cl− channels (CaCCs; TMEM16A/ANO1), Ca2+-dependent inhibition of voltage-gated K+ (KV) and ATP-sensitive K+ (KATP) channels; and Ca2+-induced-Ca2+ release through inositol 1,4,5-trisphosphate receptors (IP3Rs) participate in Ca2+-dependent positive-feedback regulation of myogenic tone. Calcium release from VSMC ryanodine receptors (RyRs) provide negative-feedback through Ca2+-spark-mediated control of BKCa channel activity, or positive-feedback regulation in cooperation with IP3Rs or CaCCs. In some arterioles, VSMC RyRs are silent. In ECs, transient receptor potential vanilloid subfamily, member 4 (TRPV4) channels produce Ca2+ sparklets that activate IP3Rs and intermediate and small conductance Ca2+ activated K+ (IKCa and sKCa) channels causing membrane hyperpolarization that is conducted to overlying VSMCs producing endothelium-dependent hyperpolarization and vasodilation. Endothelial IP3Rs produce Ca2+ pulsars, Ca2+ wavelets, Ca2+ waves and increased global Ca2+ levels activating EC sKCa and IKCa channels and causing Ca2+-dependent production of endothelial vasodilator autacoids such as NO, prostaglandin I2 and epoxides of arachidonic acid that mediate negative-feedback regulation of myogenic tone. Thus, Ca2+-dependent ion channels importantly contribute to many aspects of the regulation of myogenic tone in arterioles in the microcirculation.

Modulation of p66Shc impairs cerebrovascular myogenic tone in low renin but not low nitric oxide models of systemic hypertension

Cerebral blood flow and perfusion are tightly maintained through autoregulation despite changes in transmural pressure. Oxidative stress impairs cerebral blood flow, precipitating cerebrovascular events. Phosphorylation of the adaptor protein p66Shc increases mitochondrial-derived oxidative stress. The effect of p66Shc gain or loss of function in non-hypertensive rats is unclear. We hypothesized that p66Shc gain of function would impair autoregulation of cerebral microcirculation under physiological and pathological conditions. Three previously established transgenic (salt-sensitive background; SS) p66Shc rats were utilized, p66-Del/SS (express p66Shc with a 9-amino acid deletion), p66Shc-KO/SS (frameshift premature termination codon), and p66Shc-S36A/SS (substitution of Ser36Ala). The p66Shc-Del were also bred on Sprague-Dawley backgrounds (p66-Del/SD), and a subset was exposed to a hypertensive stimulus (L-NAME) for 4 weeks. Active and passive diameters to increasing transmural pressure were measured and myogenic tone was calculated. Myogenic responses to increasing pressure were impaired in p66Shc-Del/SS rats relative to WT/SS and knock-in substitution of S36A (P<0.05). p66-Del/SD rats did not demonstrate changes in active/passive diameters or myogenic tone relative to WT/SD, but did demonstrate attenuated passive diameter responses to higher transmural pressure relative to p66-Del/SS. 4 weeks of a hypertensive stimulus (L-NAME) did not alter active or passive diameter responses to increasing transmural pressure (P=0.86-0.99), but increased myogenic responses relative to p66-Del/SD (P<0.05). Collectively, we demonstrate the functional impact of modulation of p66Shc within the cerebral circulation and demonstrate that the genetic background of p66Shc rats largely drives changes in cerebrovascular function.

Fetal Sex and Fetal Environment Interact to Alter Diameter, Myogenic Tone, and Contractile Response to Thromboxane Analog in Rat Umbilical Cord Vessels

Fetal growth needs adequate blood perfusion from both sides of the placenta, on the maternal side through the uterine vessels and on the fetal side through the umbilical cord. In a model of intrauterine growth restriction (IUGR) induced by reduced blood volume expansion, uterine artery remodeling was blunted. The aim of this study is to determine if IUGR and fetus sex alter the functional and mechanical parameters of umbilical cord blood vessels. Pregnant rats were given a low sodium (IUGR) or a control diet for the last 7 days of pregnancy. Umbilical arteries and veins from term (22 day) fetal rats were isolated and set-up in wire myographs. Myogenic tone, diameter, length tension curve and contractile response to thromboxane analog U46619 and serotonin (5-HT) were measured. In arteries from IUGR fetuses, myogenic tone was increased in both sexes while diameter was significantly greater only in male fetuses. In umbilical arteries collected from the control group, the maximal contraction to U46619 was lower in females than males. Compared to the control groups, the maximal response decreased in IUGR male arteries and increased in female ones, thus abolishing the sexual dimorphism observed in the control groups. Reduced contractile response to U46619 was observed in the IUGR vein of both sexes. No difference between groups was observed in response to 5HT in arteries. In conclusion, the change in parameters of the umbilical cord blood vessels in response to a mild insult seems to show adaptation that favors better exchange of deoxygenated and wasted blood from the fetus to the placenta with increased myogenic tone.

Secondhand smoke exposure impairs ion channel function and contractility of mesenteric arteries

Cigarette smoke, including secondhand smoke (SHS), has significant detrimental vascular effects, but its effects on myogenic tone of small resistance arteries and the underlying mechanisms are understudied. Although it is apparent that SHS contributes to endothelial dysfunction, much less is known about how this toxicant alters arterial myocyte contraction, leading to alterations in myogenic tone. The study's goal is to determine the effects of SHS on mesenteric arterial myocyte contractility and excitability. C57BL/6J male mice were randomly assigned to either filtered air (FA) or SHS (6 hours/day, 5 days/week) exposed groups for a 4, 8, or 12-weeks period. Third and fourth-order mesenteric arteries and arterial myocytes were acutely isolated and evaluated with pressure myography and patch clamp electrophysiology, respectively. Myogenic tone was found to be elevated in mesenteric arteries from mice exposed to SHS for 12 weeks but not for 4 or 8 weeks. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 weeks of SHS exposure. Moreover, 12 weeks SHS exposed arterial myocytes have reduced total potassium channel current density, which correlates with a depolarized membrane potential (Vm). These results suggest that SHS exposure induces alterations in key ionic conductances that modulate arterial myocyte contractility and myogenic tone. Thus, chronic exposure to an environmentally relevant concentration of SHS impairs mesenteric arterial myocyte electrophysiology and myogenic tone, which may contribute to increased blood pressure and risks of developing vascular complications due to passive exposure to cigarette smoke.

Myogenic Tone in Peripheral Resistance Arteries and Arterioles: The Pressure Is On!

Resistance arteries and downstream arterioles in the peripheral microcirculation contribute substantially to peripheral vascular resistance, control of blood pressure, the distribution of blood flow to and within tissues, capillary pressure, and microvascular fluid exchange. A hall-mark feature of these vessels is myogenic tone. This pressure-induced, steady-state level of vascular smooth muscle activity maintains arteriolar and resistance artery internal diameter at 50–80% of their maximum passive diameter providing these vessels with the ability to dilate, reducing vascular resistance, and increasing blood flow, or constrict to produce the opposite effect. Despite the central importance of resistance artery and arteriolar myogenic tone in cardiovascular physiology and pathophysiology, our understanding of signaling pathways underlying this key microvascular property remains incomplete. This brief review will present our current understanding of the multiple mechanisms that appear to underlie myogenic tone, including the roles played by G-protein-coupled receptors, a variety of ion channels, and several kinases that have been linked to pressure-induced, steady-state activity of vascular smooth muscle cells (VSMCs) in the wall of resistance arteries and arterioles. Emphasis will be placed on the portions of the signaling pathways underlying myogenic tone for which there is lack of consensus in the literature and areas where our understanding is clearly incomplete.

Influence of interference of light and laser technologies on microcirculation in involutive changes of skin

In a study of 115 patients, the effect of the interference of IPL exposure using filters of 640 nm and 560 nm and the use of an erbium fractional laser with a wavelength of 1565 nm on microcirculation in patients with involutive skin changes was studied. The basis of all reparative processes is the microcirculatory link, as a unit of the trophic system of the skin. Studying the effect of phototechnologies and laser fractional exposure on microcirculation, based on the results of these studies, it is possible to develop algorithms for patient management, including additional treatment methods, as well as an algorithm for standardizing procedures, including the multiplicity and number of procedures. These studies can be the starting point for the introduction of standards that will reduce the number of complications, as well as increase the clinical effectiveness of the treatment, which will make the method more widely available. The assessment of the state of microcirculation was carried out using the method of laser Doppler flowmetry (LDF), using the mathematical analysis of the wavelet transform. Under the influence of the interference of IPL exposure using filters of 640 nm and 560 nm and the use of an erbium fractional laser with a wavelength of 1565 nm, a positive dynamics of the parameters of all parts of the microcirculation was revealed according to the LDF data. In women with spastic type of MC, the initially increased neurogenic and myogenic tone of the arterioles decreased, and endothelial function improved. In women with hyperemic type of MC, there was an improvement in neurogenic tone, correction of endothelial dysfunction, and elimination of congestion in the venular link of MC. However, the above changes were more noticeable in patients with hyperemic type of MC.

Vascular tone regulation in renal interlobar arteries of male rats is dysfunctional after intrauterine growth restriction

Intrauterine growth restriction (IUGR) due to an adverse intrauterine environment predisposes to arterial hypertension and loss of kidney function. Here we investigated whether vascular dysregulation in renal interlobar arteries (RIA) may contribute to hypertensive glomerular damage after IUGR. In rats, IUGR was induced by bilateral uterine vessel ligation. Offspring of non-operated rats served as controls (C). From postnatal day (PND) 49, blood pressure was telemetrically recorded. On PND 70, we evaluated contractile function in RIA and mesenteric arteries (MA). Additionally, blood, urine and glomerular parameters and renal collagen deposition were analyzed. IUGR-RIA not only showed loss of stretch activation in 9/11 arteries and reduced stretch-induced myogenic tone, but also a shift of the concentration-response relation of acetylcholine-induced relaxation towards lower concentrations. However, IUGR-RIA also exhibited augmented contractions through phenylephrine (PE). Systemic mean arterial pressure [mean differences 4.8 (daytime) and 5.7 mmHg (night)], mean glomerular area (IUGR, 9754 ± 338; C, 8395 ± 227 µm2) and urinary protein/creatinine ratio (IUGR, 1.67 ± 0.13; C, 1.26 ± 0.10 g/g) were elevated after IUGR. We conclude that male IUGR rat offspring may have increased vulnerability towards hypertensive glomerular damage due to loss of myogenic tone and augmented endothelium-dependent relaxation in RIA.