Vasomotor Responses Research Articles

Hyperthermia and dehydration: their independent and combined influences on physiological function during rest and exercise.

This experiment was designed to quantify the independent and combined influences of hyperthermia and dehydration on effector control during rest and exercise. To achieve that, whole-body hydration of healthy adults (N = 8) was manipulated into each of three states (euhydrated, 3% and 5% dehydrated), and then clamped within each of two thermal states (normothermia [mean body temperature: 36.1°C] and moderate hyperthermia [mean body temperature: 38.2°C]). Those treatment combinations provided six levels of physiological strain, with resting physiological data collected at each level. The effects of isothermal, thermally unclamped and incremental exercise were then investigated in normothermic individuals during each level of hydration. At rest, dehydration alone reduced urine flows by 83% (3% dehydrated) and 93% (5% dehydrated), while the reduction accompanying euhydrated hyperthermia was 86%. The sensitivities of renal water conservation to 3% dehydration (-21%mOsm-1kg H2O-1) and moderate hyperthermia (-40%°C-1) were independent and powerful. Evidence was found for different renal mechanisms governing water conservation between those treatments. Cutaneous vasomotor and central cardiac responses were unresponsive to dehydration, but highly sensitive to passive thermal stress. Dehydration did not impair either whole-body or regional sweating during rest or exercise, and not even during incremental cycling to volitional exhaustion. In all instances, the physiological impact of these thermal- and hydration-state stresses was independently expressed, with no evidence of interactive influences. Renal water-conservation was independently and powerfully modified, exposing possible between-treatment differences in sodium reabsorption.

Cerebral Hemodynamic Response To Menstrual Cycle In Migraine

Objective: Menstrually related migraine (MRM) occurs in relation to menstrual cycles. We investigated the cerebral hemodynamic response to the menstrual cycle in nonmenstrually related migraines (nMRM), MRM and healthy controls.
 Methods: 22 nMRM, 20 MRM patients in an attack-free interval and 20 healthy volunteers were included in our study. TCD recordings were made during the follicular and luteal phases of the hormonal cycle and mean flow velocity values of middle and posterior cerebral arteries were studied. Cerebral vasomotor reactivity (CVR) was evaluated by breath holding index (BHI) and visually evoked blood flow (VEBF) changes in both phases of the same menstrual cycle.
 Results: Mean flow veloticities and hormone levels were not different between groups. Right BHI and bilateral VEBF values were significantly lower in both of the migraine groups. The physiological elevation of CVR in the luteal phase was detected in the control and nMRM groups, but not in the MRM group.
 Conclusion: The cerebral hemaodynamics were affected in both MRM and nMRM. Additionally the physiological CVR to menstrual cycle was impaired in MRM. The impairment in cerebral hemodynamic response to the menstrual cycle in MRM needs further research to discover the underlying pathophysiology.

Conceptualizing Conduction as a Pliant Vasomotor response: Impact of Ca2+ fluxes and Ca2+ Sensitization.

Coordinating blood flow to active tissue requires vasomotor responses to conduct among resistance arteries. Vasomotor spread is governed by the electrical and mechanical properties of vessels; the latter being linked to the sigmoid relations between membrane potential (VM), [Ca2+], and smooth muscle contractility. Proteins guiding electrical-to-tone translation are subject to regulation; thus, vasomotor conduction could be viewed as "pliant" to the current regulatory state. Using simple in silico approaches, we explored vasomotor pliancy and how the regulation of contractility impacts conduction along a skeletal muscle artery and a branching cerebrovascular network. Initial simulations revealed how limited electromechanical linearity affects the translation of electrical spread into arterial tone. Subtle changes to the VM-[Ca2+] or [Ca2+]-diameter relationship, akin to regulatory alterations in Ca2+ influx and Ca2+ sensitivity, modified the distance and amplitude of the conducted vasomotor response. Simultaneous changes to both relationships, consistent with agonist stimulation, augmented conduction although the effect varied with stimulus strength and polarity (depolarization vs hyperpolarization). Final simulations using our cerebrovascular network revealed how localized changes to the VM-[Ca2+] or [Ca2+]-diameter relationships could regionally shape conduction without interfering with the electrical spread. We conclude that regulatory changes to key effector proteins (e.g. L-type Ca2+ channels, myosin light chain phosphatase), integral to voltage translation, not only impact conducted vasomotor tone but likely blood flow delivery to active tissues.

Multiorgan contribution to non-shivering and shivering thermogenesis and vascular responses during gradual cold exposure in humans.

Human brown adipose tissue (BAT) is known to be a significant thermoeffector in non-shivering thermogenesis (NST), albeit with individual variations in the BAT activity. We hypothesized that humans with less BAT would have more contribution from the skeletal muscle (SM) to NST or earlier shivering onset and greater vasoconstriction to compensate for less BAT-mediated thermogenesis. Eighteen males participated in this study. Their BAT activity and detectable volume were investigated. A gradual cold exposure was conducted for inducing NST at 18.6°C and initiating shivering at 11.6°C. The energy expenditure, electromyograph of the pectoralis major, skin blood flow, and rectal (Tre) and skin temperatures were evaluated. BAT volume significantly correlated with the change in metabolic heat production during mild cold phase relative to baseline (NST; r = 0.562, P < 0.05), but not with shivering initiation phase (NST+ ST). SM mass correlated with baseline metabolic heat production (Mbase; r = 0.839, P < 0.01) but not with NST or NST + ST. A positive correlation was noted between BAT volume and Tre at the end of the 18.6°C exposure period (r = 0.586, P < 0.05), which positively correlated with shivering onset time (r = 0.553, P < 0.05). The skin blood flow, mean skin temperature, and forearm and finger skin temperature difference at the end of the 18.6°C exposure period did not correlate with NST or BAT volume. BAT volume positively correlated with NST. Notably, lower Tre in individuals with less BAT volume induced earlier shivering onset for offsetting the less NST. Whereas, no correlation between metabolic and vasomotor responses was observed.

Comprehensive Characterization of the Vascular Effects of Cisplatin-Based Chemotherapy in Patients With Testicular Cancer

BackgroundCisplatin-based chemotherapy increases the risk of cardiovascular and renal disease. ObjectivesWe aimed to define the time course, pathophysiology, and approaches to prevent cardiovascular disease associated with cisplatin-based chemotherapy. MethodsTwo cohorts of patients with a history of testicular cancer (n = 53) were recruited. Cohort 1 consisted of 27 men undergoing treatment with: 1) surveillance; 2) 1 to 2 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (low-intensity cisplatin); or 3) 3 to 4 cycles of BEP (high-intensity cisplatin). Endothelial function (percentage flow-mediated dilatation) and cardiovascular biomarkers were assessed at 6 visits over 9 months. Cohort 2 consisted of 26 men previously treated 1 to 7 years ago with surveillance or 3 to 4 cycles BEP. Vasomotor and fibrinolytic responses to bradykinin, acetylcholine, and sodium nitroprusside were evaluated using forearm venous occlusion plethysmography. ResultsIn cohort 1, the percentage flow-mediated dilatation decreased 24 h after the first cisplatin dose in patients managed with 3 to 4 cycles BEP (10.9 ± 0.9 vs. 16.7 ± 1.6; p < 0.01) but was unchanged from baseline thereafter. Six weeks after starting 3 to 4 cycles BEP, there were increased serum cholesterol levels (7.2 ± 0.5 mmol/l vs. 5.5 ± 0.2 mmol/l; p = 0.01), hemoglobin A1c (41.8 ± 2.0 mmol/l vs. 35.5 ± 1.2 mmol/l; p < 0.001), von Willebrand factor antigen (62.4 ± 5.4 mmol/l vs. 45.2 ± 2.8 mmol/l; p = 0.048) and cystatin C (0.91 ± 0.07 mmol/l vs. 0.65 ± 0.09 mmol/l; p < 0.01). In cohort 2, intra-arterial bradykinin, acetylcholine, and sodium nitroprusside caused dose-dependent vasodilation (p < 0.0001). Vasomotor responses, endogenous fibrinolytic factor release, and cardiovascular biomarkers were not different in patients managed with 3 to 4 cycles of BEP versus surveillance. ConclusionsCisplatin-based chemotherapy induces acute and transient endothelial dysfunction, dyslipidemia, hyperglycemia, and nephrotoxicity in the early phases of treatment. Cardiovascular and renal protective strategies should target the early perichemotherapy period. (Clinical Characterisation of the Vascular Effects of Cis-platinum Based Chemotherapy in Patients With Testicular Cancer [VECTOR], NCT03557177; Intermediate and Long Term Vascular Effects of Cisplatin in Patients With Testicular Cancer [INTELLECT], NCT03557164)

Cerebral Vasomotor Reactivity in Amnestic Mild Cognitive Impairment.

Cerebral blood flow (CBF) is sensitive to changes in arterial CO2, referred to as cerebral vasomotor reactivity (CVMR). Whether CVMR is altered in patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer disease (AD), is unclear. To determine whether CVMR is altered in aMCI and is associated with cognitive performance. Fifty-three aMCI patients aged 55 to 80 and 22 cognitively normal subjects (CN) of similar age, sex, and education underwent measurements of CBF velocity (CBFV) with transcranial Doppler and end-tidal CO2 (EtCO2) with capnography during hypocapnia (hyperventilation) and hypercapnia (rebreathing). Arterial pressure (BP) was measured to calculate cerebrovascular conductance (CVCi) to normalize the effect of changes in BP on CVMR assessment. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and neuropsychological tests focused on memory (Logical Memory, California Verbal Learning Test) and executive function (Delis-Kaplan Executive Function Scale; DKEFS). At rest, CBFV and MMSE did not differ between groups. CVMR was reduced by 13% in CBFV% and 21% in CVCi% during hypocapnia and increased by 22% in CBFV% and 20% in CVCi% during hypercapnia in aMCI when compared to CN (all p < 0.05). Logical Memory recall scores were positively correlated with hypocapnia (r = 0.283, r = 0.322, p < 0.05) and negatively correlated with hypercapnic CVMR measured in CVCi% (r = -0.347, r = -0.446, p < 0.01). Similar correlations were observed in D-KEFS Trail Making scores. Altered CVMR in aMCI and its associations with cognitive performance suggests the presence of cerebrovascular dysfunction in older adults who have high risks for AD.

Erenumab does not alter cerebral hemodynamics and endothelial function in migraine without aura.

To assess whether erenumab influences cerebral vasomotor reactivity and flow-mediated dilation in migraine patients. Consecutive migraineurs prescribed erenumab at our Headache Centre and age and sex-matching controls were invited to participate in this observational longitudinal study. Patients were evaluated for cerebral vasomotor reactivity to hypercapnia (breath-holding index) in middle and posterior cerebral arteries and for brachial corrected flow mediated dilation at baseline (T0), after 2 weeks from the first erenumab injection (T2) and after 2 weeks from the fourth Erenumab injection (T18). Patients displaying a reduction of at least 50% in monthly migraine days after completing the fourth month of therapy were classified as responders. Sixty patients and 25 controls agreed to participate. Middle and posterior cerebral artery mean flow velocities, breath-holding index and flow-mediated dilation did not differ at T0 and from T0 to T2 in patients and controls. In patients, we neither observed a variation of the explored variables from T0 to T18 nor an interaction between evaluation times (T0-T2 or T0-T18) and chronic condition at T0, responder state or erenumab fourth dose. Our findings demonstrate that erenumab preserves cerebral vasomotor reactivity and flow-mediated dilation in migraineurs without aura.

Long-Term and Acute Benefits of Reduced Sitting on Vascular Flow and Function.

Sedentary behavior increases the risk for cardiovascular and cerebrovascular disease. To understand potential benefits and underlying mechanisms, we examined the acute and long-term effect of reduced sitting intervention on vascular and cerebrovascular function. This prospective study included 24 individuals with increased cardiovascular risk (65 ± 5 yr, 29.8 ± 3.9 kg·m-2). Before and after 16-wk reduced sitting, using a mobile health device with vibrotactile feedback, we examined (i) vascular function (flow-mediated dilation [FMD]), (ii) cerebral blood flow velocity (CBFv, transcranial Doppler), and (iii) cerebrovascular function (cerebral autoregulation [CA] and cerebral vasomotor reactivity [CVMR]). To better understand potential underlying mechanisms, before and after intervention, we evaluated the effects of 3 h sitting with and without light-intensity physical activity breaks (every 30 min). The first wave of participants showed no change in sedentary time (n = 9, 10.3 ± 0.5 to 10.2 ± 0.5 h·d-1, P = 0.87). Upon intervention optimization by participants' feedback, the subsequent participants (n = 15) decreased sedentary time (10.2 ± 0.4 to 9.2 ± 0.3 h·d-1, P < 0.01). This resulted in significant increases in FMD (3.1% ± 0.3% to 3.8% ± 0.4%, P = 0.02) and CBFv (48.4 ± 2.6 to 51.4. ±2.6 cm·s-1, P = 0.02), without altering CA or CVMR. Before and after the 16-wk intervention, 3-h exposure to uninterrupted sitting decreased FMD and CBFv, whereas physical activity breaks prevented a decrease (both P < 0.05). CA and CVMR did not change (P > 0.20). Long-term reduction in sedentary behavior improves peripheral vascular function and cerebral blood flow and acutely prevents impaired vascular function and decreased cerebral blood flow. These results highlight the potential benefits of reducing sedentary behavior to acutely and chronically improve cardio- or cerebrovascular risk.

Atherogenic diet-diminished endothelial glycocalyx contributes to impaired vasomotor properties in rat.

Hypercholesterolemia- and atherosclerosis-caused vasomotor property dysfunction may be involved in many clinic manifestations of atherosclerosis, including angina, acute myocardial infarction, and sudden cardiac death. However, its underlying mechanism is not clear. The endothelial glycocalyx is a protective surface layer on the endothelial cells, serving as a molecular sieve, cell adhesion modulator, and mechanosensor for blood flow. In the present study, we demonstrated by confocal microscopy in Sprague-Dawley (SD) male rats fed a 12-wk high-cholesterol diet (HC) compared with the normal diet (NC) that the dimension of the endothelial glycocalyx reduced significantly in both the common carotid artery (2.89 ± 0.41 µm and 3.25 ± 0.44 μm, respectively) and the internal sinus region (2.35 ± 0.07 µm and 3.46 ± 0.86 μm, respectively). Furthermore, we showed by real-time PCR that this dimension modification of endothelial glycocalyx may be attributed to a significant downregulation of heparan sulfate proteoglycan (HSPG)-related genes, including syndecan-3, glypican-1, and EXT1, not resulting from an enhanced shedding of sulfated glycosaminoglycans (sGAGs) from the vessel wall to the plasma. Meanwhile, the mean contraction and relaxation forces of the common carotid artery with responses to norepinephrine (NE) and acetylcholine (ACh) decreased ~0.34- and 0.13-fold, respectively, accompanied by a lower level of nitric oxide (NO) release. These findings suggest that the atherogenic high cholesterol diet diminished endothelial glycocalyx and disturbed the local NO release, thus contributing to the impaired vasomotor properties of the vessel.NEW & NOTEWORTHY Twelve-week high-cholesterol (HC) diet reduces the thickness of the endothelial glycocalyx in Sprague-Dawley (SD) male rats, which is mainly attributed to a downregulation of heparan sulfate proteoglycan-related genes (syndecan-3, glypican-1, EXT1), not resulting from an enhanced shedding of sulfated glycosaminoglycans (sGAGs) into the plasma. HC-diminished glycocalyx may disturb its mechanotransduction of local shear stress, lower nitric oxide (NO) release, and impair vasomotor responses to norepinephrine (NE) and acetylcholine (ACh).

Cerebral Hemodynamic Changes to Transcranial Doppler in Asymptomatic Patients with Fabry's Disease.

Background: Patients with Fabry’s disease (FD) may be asymptomatic or show a spectrum of clinical manifestations, including cerebrovascular disease, mainly affecting posterior circulation. Few and conflicting studies on cerebral blood flow (CBF) velocity by transcranial Doppler sonography (TCD) in asymptomatic FD (aFD) subjects have been published. Our study aims to assess TCD in aFD subjects to identify any preclinical CBF change. Methods: A total of 30 aFD subjects were consecutively recruited and compared to 28 healthy controls. Brain magnetic resonance imaging was normal in all participants. TCD was used to study blood flow velocity and indices of resistance of intracranial arteries from the middle cerebral artery (MCA), bilaterally, and from the basilar artery (BA). Cerebral vasomotor reactivity (CVR) was also evaluated from MCA. Results: No difference was found between groups for MCA parameters of CBF velocity and CVR. Compared to controls, a higher mean blood flow velocity and a lower resistance index from BA were observed in FD subjects. No correlation was found between any BA-derived TCD parameter and the level of lyso-globotriaosylceramide. Conclusions: aFD subjects show evidence of altered CBF velocity in posterior circulation. Preclinical detection of neurovascular involvement in FD might allow appropriate management and prevention of future cerebrovascular complications and disability.

Lack of Connexins 40 and 45 Reduces Local and Conducted Vasoconstrictor Responses in the Murine Afferent Arterioles.

The juxtaglomerular apparatus (JGA) is an essential structure in the regulation of renal function. The JGA embodies two major functions: tubuloglomerular feedback (TGF) and renin secretion. TGF is one of the mechanisms mediating renal autoregulation. It is initiated by an increase in tubular NaCl concentration at the macula densa cells. This induces a local afferent arteriolar vasoconstriction and a conducted response that can be measured several 100 μm upstream from the juxtaglomerular segment. This spread of the vasomotor response into the surrounding vasculature likely plays a key role in renal autoregulation, and it requires the presence of gap junctions, intercellular pores based on connexin (Cx) proteins. Several Cx isoforms are expressed in the JGA and in the arteriolar wall. Disruption of this communication pathway is associated with reduced TGF, dysregulation of renin secretion, and hypertension. We examine if the absence of Cx40 or Cx45, expressed in the endothelial and vascular smooth muscle cells respectively, attenuates afferent arteriolar local and conducted vasoconstriction. Afferent arterioles from wildtype and Cx-deficient mice (Cx40 and Cx45) were studied using the isolated perfused juxtamedullary nephron preparation. Vasoconstriction was induced via electrical pulse stimulation at the glomerular entrance. Inner afferent arteriolar diameter was measured locally and upstream to evaluate conducted vasoconstriction. Electrical stimulation induced local vasoconstriction in all groups. The local vasoconstriction was significantly smaller when Cx40 was absent. The vasoconstriction decreased in magnitude with increasing distance from the stimulation site. In both Cx40 and Cx45 deficient mice, the vasoconstriction conducted a shorter distance along the vessel compared to wild-type mice. In Cx40 deficient arterioles, this may be caused by a smaller local vasoconstriction. Collectively, these findings imply that Cx40 and Cx45 are central for normal vascular reactivity and, therefore, likely play a key role in TGF-induced regulation of afferent arteriolar resistance.

Endothelial Ca2+ signaling-dependent vasodilation through transient receptor potential channels.

Ca2+ signaling of endothelial cells plays a critical role in controlling blood flow and pressure in small arteries and arterioles. As the impairment of endothelial function is closely associated with cardiovascular diseases (e.g., atherosclerosis, stroke, and hypertension), endothelial Ca2+ signaling mechanisms have received substantial attention. Increases in endothelial intracellular Ca2+ concentrations promote the synthesis and release of endothelial-derived hyperpolarizing factors (EDHFs, e.g., nitric oxide, prostacyclin, or K+ efflux) or directly result in endothelial-dependent hyperpolarization (EDH). These physiological alterations modulate vascular contractility and cause marked vasodilation in resistance arteries. Transient receptor potential (TRP) channels are nonselective cation channels that are present in the endothelium, vascular smooth muscle cells, or perivascular/sensory nerves. TRP channels are activated by diverse stimuli and are considered key biological apparatuses for the Ca2+ influx-dependent regulation of vasomotor reactivity in resistance arteries. Ca2+-permeable TRP channels, which are primarily found at spatially restricted microdomains in endothelial cells (e.g., myoendothelial projections), have a large unitary or binary conductance and contribute to EDHFs or EDH-induced vasodilation in concert with the activation of intermediate/small conductance Ca2+-sensitive K+ channels. It is likely that endothelial TRP channel dysfunction is related to the dysregulation of endothelial Ca2+ signaling and in turn gives rise to vascular-related diseases such as hypertension. Thus, investigations on the role of Ca2+ dynamics via TRP channels in endothelial cells are required to further comprehend how vascular tone or perfusion pressure are regulated in normal and pathophysiological conditions.

Hydrogen Protons Modulate Perivascular Axo-axonal Interactions in the Middle Cerebral Artery of Rats.

Previous studies have demonstrated that nicotine can induce relaxation of the middle cerebral artery (MCA). However, whether this relaxation is associated with the activity of sensory calcitonin gene-related peptide (CGRP) nerves and whether this is modulated by hydrogen protons (H), facilitating the release of CGRP from sensory CGRPergic nerve terminals in the MCA, remains unclear. In this study, we examined the role of H in the modulation of neurogenic vasomotor responses in the rat-isolated endothelium-denuded MCA. Wire myography was used to measure vasoreactivity and indicated that nicotine-induced relaxation was sensitive to tetrodotoxin and lidocaine and drastically reduced levels of guanethidine (an adrenergic neuronal blocker), N-nitro-L-arginine (L-NNA), CGRP8-37, vasoactive intestinal polypeptide (VIP)6-28, capsaicin, capsazepine (a transient receptor potential vanilloid-1 inhibitor), and tetraethylammonium. However, this nicotine-induced relaxation was not sensitive to propranolol. Lowering the pH of the buffer solution with HCl caused pH-dependent vasorelaxation and deceased intracellular pH in the MCA rings, which was sensitive to L-NNA, CGRP8-37, VIP6-28, capsazepine, 4-aminopyridine (a voltage-gated potassium channel antagonist), and paxilline (a large conductance Ca-activated K channel antagonist). However, HCl-induced relaxation was not inhibited by glibenclamide (an ATP-sensitive K channel blocker). These results suggested that electrical and chemical activation of cerebral perivascular adrenergic nerves led to the release of H, which then facilitated the release of NO, VIP, and CGRP, resulting in vasorelaxation. Lowering the pH of the buffer solution caused potassium channels of vascular smooth muscle cells and perivascular nerves to open. In conclusion, our results demonstrated that H may act as a modulator on MCA perivascular nerves and/or smooth muscles.

Mechanisms Involved in Lacunar Infarction and Their Role in Early Neurological Deterioration

Background The mechanisms of lacunar infarction are still unclear and may be heterogenous. We aimed to investigate the presence of parent artery atheroma, cerebral vasodilatory function, and blood-brain barrier (BBB) breakdown and their role in the development of early neurological deterioration (END) in patients with acute lacunar infarction. Methods Patients with acute lacunar infarction prospectively underwent transcranial Doppler breath-holding test, contrast-enhanced f luid-attenuated inversion recovery magnetic resonance imaging, and magnetic resonance angiography with/without high-resolution vessel wall imaging to determine the cerebral vasomotor reactivity to carbon dioxide (CO2-CVR) of the symptomatic artery, BBB breakdown, and the presence of branch atheromatous disease in the parent artery, respectively, before the development of END. We compared the presence of each mechanism between patients who developed END and those without END and the role in predicting END between mechanisms. Results Among the 41 patients included, three (7.3%) experienced END. Reduced CO2-CVR, branch atheromatous disease, and widespread BBB breakdown were observed in eight (19.5%), 10 (24.4%), and 11 patients (26.8%), respectively. Among these factors, CO2-CVR was significantly lower in patients with END than in those without END (breath-holding index, 0.64 [interquartile range, 0.47–0.70] vs. 1.05 [0.81–1.33], p=0.028) and best predicted END (area under the curve=0.889; 95% confidence interval, 0.779–0.999; p<0.001). Conclusion Cerebral vasodilatory dysfunction is associated with END in patients with acute lacunar infarction. Our study suggests that CO2-CVR testing has a role in the risk stratification of lacunar infarction, and a confirmatory study is required in the future. Key words: Stroke; Lacunar infarction; Cerebral small vessel diseases; Transcranial Doppler ultrasonography; Blood-brain barrier

Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging.

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide–cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1Δ/- mice, can be used as a tool to accelerate aging. Ercc1Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO–cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1Δ/- mice. Ercc1Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1Δ/- mice developed decreased reactive hyperemia, and diminished NO–cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO–cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.

Extracellular creatine kinase may modulate purinergic signalling.

Extracellular purine nucleotides and nucleosides including ADP and ATP regulate a wide array of physiological processes including platelet aggregation, vasomotor responses and inflammation through specific purinergic receptors. In the recent years, a strong association has been reported between circulating cytoplasmic-type creatine kinase and adverse clinical outcomes such as major bleeding, hypertension and obesity. Therefore, it is proposed that extracellular CK may modulate purinergic signalling through its ADP binding and/or ATP-generating effect.

The short-term effects of sedentary behaviour on cerebral hemodynamics and cognitive performance in older adults: a cross-over design on the potential impact of mental and/or physical activity

BackgroundSedentary behaviour might be a potential risk factor for cognitive decline. However, the short-term effects of sedentary behaviour on (cerebro) vascular and cognitive performance in older people are unknown.MethodsWe used a cross-over design with 22 older adults (78 years, 9 females) to assess the short-term hemodynamic and cognitive effects of three hours uninterrupted sitting and explored if these effects can be counteracted with regular (every 30 min) two-minute walking breaks. In addition, we investigated if low versus high mental activity during the three hours of sitting modified these effects. Before and after each condition, alertness, executive functioning, and working memory were assessed with the Test of Attentional Performance battery. Additionally, cerebral blood flow velocity (Transcranial Doppler) and blood pressure (Finapres) were measured in rest, and during sit-to-stand and CO2 challenges to assess baroreflex sensitivity, cerebral autoregulation, and cerebral vasomotor reactivity.ResultsNo short-term differences were observed in cognitive performance, cerebral blood flow velocity, baroreflex sensitivity, cerebral autoregulation, or cerebral vasomotor reactivity across time, or between conditions. Blood pressure and cerebrovascular resistance increased over time (8.6 mmHg (5.0;12.1), p < 0.001), and 0.23 in resistance (0.01;0.45), p = 0.04). However, these effects were not mitigated by mental activity or by short walking breaks to interrupt sitting.ConclusionsIn older individuals, three hours of sitting did not influence cognitive performance or cerebral perfusion. However, the sitting period increased blood pressure and cerebrovascular resistance, which are known to negatively impact brain health in the long-term. Importantly, we found that these effects in older individuals cannot be mitigated by higher mental activity and/or regular walking breaks.Trial registrationClinical trial registration URL: https://www.toetsingonline.nl/. Unique identifier: NL64309.091.17. Date of registration: 06–02–2018.

Cytochrome P450 epoxygenase-derived 5,6-epoxyeicosatrienoic acid relaxes pulmonary arteries in normoxia but promotes sustained pulmonary vasoconstriction in hypoxia.

The aim of the study was to investigate the role of cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in sustained hypoxic pulmonary vasoconstriction (HPV). Vasomotor responses of isolated mouse intrapulmonary arteries (IPAs) were assessed using wire myography. Key findings were verified by haemodynamic measurements in isolated perfused and ventilated mouse lungs. Pharmacological inhibition of EET synthesis with MS-PPOH, application of the EET antagonist 14,15-EEZE or deficiency of CYP2J isoforms suppressed sustained HPV. In contrast, knockdown of EET-degrading soluble epoxide hydrolase or its inhibition with TPPU augmented sustained HPV almost twofold. All EET regioisomers elicited relaxation in IPAs pre-contracted with thromboxane mimetic U46619. However, in the presence of KCl-induced depolarization, 5,6-EET caused biphasic contraction in IPAs and elevation of pulmonary vascular tone in isolated lungs, whereas other regioisomers had no effect. In patch-clamp experiments, hypoxia elicited depolarization in pulmonary artery smooth muscle cells (PASMCs), and 5,6-EET evoked inward whole cell currents in PASMCs depolarized to the hypoxic level, but not at their resting membrane potential. The EET pathway substantially contributes to sustained HPV in mouse pulmonary arteries. 5,6-EET specifically appears to be involved in HPV, as it is the only EET regioisomer able to elicit not only relaxation, but also sustained contraction in these vessels. 5,6-EET-induced pulmonary vasoconstriction is enabled by PASMC depolarization, which occurs in hypoxia. The discovery of the dual role of 5,6-EET in the regulation of pulmonary vascular tone may provide a basis for the development of novel therapeutic strategies for treatment of HPV-related diseases.

Cerebral hemodynamics in patients with multiple sclerosis

Background and PurposeMultiple sclerosis (MS) is a demyelinating disease of the central nervous system. Although the currently predominant view is that of an autoimmune inflammatory condition, changes in brain vasculature can occur and contribute to pathophysiology. The aim of this study was to evaluate cerebral hemodynamics in patients with MS and explore its relationship with disease status. MethodsPatients with MS and age- and sex- matched healthy controls were recruited. All participants underwent assessment of cerebral hemodynamics through transcranial Doppler ultrasonography. Cerebral vasomotor reactivity (CVR) to hypercapnia was measured by the breath-holding index (BHI). ResultsA total of 80 patients with MS and 80 healthy controls were recruited. BHI values obtained in healthy controls, relapsing-remitting (RR)-MS and secondary progressive (SP)-MS patients were 1.15±0.11, 0.87±0.18 and 0.51±0.20, respectively (p<0.001). Group-wise, patients showed decreased CVR in comparison to controls and BHI values were significantly lower in SP-MS than in RR-MS patients. At linear regression analysis, the disease form was significantly associated with cerebral hemodynamics being the SP phenotype an independent predictor of lower BHI values [β=-0.36, 95% confidence interval (CI): -0.44 to -0.27, p<0.001; adjusted β=-0.37, 95% CI: -0.50 to -0.23, p<0.001). ConclusionsCerebrovascular hemodynamic insufficiency in MS may be secondary to the downstream effects of neuro-inflammatory cascades.

The pericyte connectome: spatial precision of neurovascular coupling is driven by selective connectivity maps of pericytes and endothelial cells and is disrupted in diabetes

Functional hyperemia, or the matching of blood flow with activity, directs oxygen and nutrients to regionally firing neurons. The mechanisms responsible for this spatial accuracy remain unclear but are critical for brain function and establish the diagnostic resolution of BOLD-fMRI. Here, we described a mosaic of pericytes, the vasomotor capillary cells in the living retina. We then tested whether this net of pericytes and surrounding neuroglia predicted a connectivity map in response to sensory stimuli. Surprisingly, we found that these connections were not only selective across cell types, but also highly asymmetric spatially. First, pericytes connected predominantly to other neighboring pericytes and endothelial cells, and less to arteriolar smooth muscle cells, and not to surrounding neurons or glia. Second, focal, but not global stimulation evoked a directional vasomotor response by strengthening connections along the feeding vascular branch. This activity required local NO signaling and occurred by means of direct coupling via gap junctions. By contrast, bath application of NO or diabetes, a common microvascular pathology, not only weakened the vascular signaling but also abolished its directionality. We conclude that the exclusivity of neurovascular interactions may thus establish spatial accuracy of blood delivery with the precision of the neuronal receptive field size, and is disrupted early in diabetes.