Arteriolar Dilation In Response Research Articles

Elevated plasma aldosterone impairs functional hyperemia and cognitive function

Aldosterone, a steroid hormone, plays an important role in blood pressure homeostasis and the maintenance of plasma electrolyte levels by activating the mineralocorticoid receptor (MR) in renal distal tubule and collecting duct epithelial cells. Recent studies revealed that MRs are also expressed in other tissues, including cardiac myocytes, vascular smooth muscle cells, and vascular endothelial cells (EC), and that elevated plasma aldosterone, termed hyperaldosteronemia (HA), has deleterious effects on the cardiovascular system. HA is present in 10-30% of hypertensive patients and unrecognized and asymptomatic HA is estimated to occur in > 10% of individuals with normal blood pressure. Despite the high prevalence of HA, little is known about its impact on cerebral blood flow (CBF) regulation and brain health. This study focused on the physiological processes that support the on-demand delivery of blood to regions of heightened neuronal activity (functional hyperemia). Specifically, we examined the impact of HA on the recently discovered novel mechanism, termed capillary-to-arteriole signaling, through which capillaries and their strong inward rectifier K+ (Kir 2.1) channels play a significant role in functional hyperemia. Importantly, early deficits in functional hyperemia are a hallmark of small vessel diseases of the brain, which are significant contributors to cognitive impairment and dementia. Employing HA model mice, we examined the impact of HA on functional hyperemia, capillary-to-arteriole signaling, Kir2.1 channel activity in freshly isolated capillary ECs (cECs), and cognitive function. Functional hyperemia, measured as whisker stimulation-induced CBF increases using laser Doppler flowmetry, was impaired in HA animals compared to vehicle-treated animals. Retrograde capillary-to-arteriole signaling, evaluated as upstream arteriolar dilation in response to capillary stimulation with 10 mM K+ in Capillary-Parenchymal Arteriole (CaPA), preparations was significantly attenuated in HA mice. Furthermore, cEC Kir2.1 channel currents, recorded using the conventional whole-cell configuration of the patch-clamp technique, were significantly smaller in HA mice compared to vehicle-treated mice. Further, HA model animals obtained lower scores in the Novel Object Recognition test, indicating that cognitive function in the form of memory retention may be impacted by elevated plasma aldosterone. These data suggest that HA impairs functional hyperemia and cognitive function, and that HA may be a novel risk factor for vascular cognitive impairment. This work was supported by The National Institute of Health (P20-GM-135007 to MK and R01-HL-142888 to GCW). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Biomarkers of microvascular dysfunction and cerebral white matter connectivity: The Maastricht Study

AbstractBackgroundMicrovascular dysfunction may contribute to the development of various cerebral disorders, including cognitive dysfunction, dementia, and certain forms of depression. The suggested mechanism through which microvascular dysfunction contributes to these disorders is by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and cerebral white matter connectivity.MethodWe used cross‐sectional data from The Maastricht Study, a Dutch population‐based cohort (n = 4,326, mean±SD age 59.4±8.6 years, 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers (CRAE and CRVE), a composite score of flicker light‐induced retinal arteriolar and venular dilation response, and a composite score of plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble E‐selectin (sE‐selectin) and von Willebrand factor (vWF)). White matter connectivity was calculated from 3T diffusion MRI to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient and local efficiency) of cerebral white matter connections.ResultA higher endothelial dysfunction composite score was associated with a longer characteristic path length (beta per SD: 0.066 (95% confidence interval: 0.017; 0.114)) after adjustment for sociodemographic, lifestyle and cardiovascular factors, but not with any of the other white matter connectivity measures. All other measures of microvascular dysfunction were not associated with any of the connectivity measures after adjustments.ConclusionThe present study suggests that microvascular dysfunction, as quantified by a set of various measures, is not consistently associated with cerebral white matter connectivity. Only a composite score of plasma biomarkers of endothelial dysfunction was associated with a longer characteristic path length, with a longer characteristic path length being indicative for a topographically less integrated and less efficient cerebral network. Future cross‐sectional and longitudinal studies are needed to further understand the role of microvascular dysfunction in the development of cerebral disorders.

Retinal microvascular function is associated with the cerebral microcirculation as determined by intravoxel incoherent motion MRI

Background and aimsThe easily accessible retinal vessels provide a unique opportunity to study a proxy for cerebral small vessels. Associations between retinal vessel diameters and macrostructural brain white matter changes have already been demonstrated. Alterations in microvascular function, likely precede these structural abnormalities. We examined whether retinal microvascular function is related to cerebral microvascular properties, assessed by the intravoxel incoherent motion (IVIM) effect in brain MRI. MethodsSeventy participants (age 60 ± 8 years, 41% women) from the population-based Maastricht Study underwent brain IVIM diffusion imaging (3 Tesla) to determine the microvascular measures f (perfusion volume fraction) and D* (pseudo-diffusion of circulating blood). The retinal arteriolar and venular dilation response to flicker light stimulation were measured by a dynamic vessel analyzer. Linear regression analysis was used to investigate associations between retinal vasoreactivity and IVIM measures in white matter hyperintensities (WMH), normal-appearing white matter (NAWM) and cortical gray matter (CGM). ResultsMore retinal arteriolar dilation was significantly associated with stronger pseudo-diffusion (D*) in the NAWM and CGM (β 0.280 [95% CI 0.084–0.475], and β 0.310 [95% CI 0.091–0.528], respectively), but not with the cerebral blood volume fraction (f). No associations were observed between retinal venular dilation response and cerebrovascular IVIM measures. ConclusionsVariations in retinal arteriolar microvascular function and microcirculatory properties in the brain are linked. The retina could serve as a proxy for early detection of brain microvascular dysfunction.

Extracerebral microvascular dysfunction is related to brain MRI markers of cerebral small vessel disease: The Maastricht Study

BackgroundCerebral small vessel disease (cSVD) is a late consequence of cerebral microvascular dysfunction (MVD). MVD is hard to measure in the brain due to its limited accessibility. Extracerebral MVD (eMVD) measures can give insights in the etiology of cerebral MVD, as MVD may be a systemic process. We aim to investigate whether a compound score consisting of several eMVD measures is associated with structural cSVD MRI markers.MethodsCross-sectional data of the population-based Maastricht Study was used (n = 1872, mean age 59 ± 8 years, 49% women). Measures of eMVD included flicker light-induced retinal arteriolar and venular dilation response (retina), albuminuria and glomerular filtration rate (kidney), heat-induced skin hyperemia (skin), and plasma biomarkers of endothelial dysfunction (sICAM-1, sVCAM-1, sE-selectin, and von Willebrand factor). These measures were standardized into z scores and summarized into a compound score. Linear and logistic regression analyses were used to investigate the associations between the compound score and white matter hyperintensity (WMH) volume, and the presence of lacunes and microbleeds, as measured by brain MRI.ResultsThe eMVD compound score was associated with WMH volume independent of age, sex, and cardiovascular risk factors (St β 0.057 [95% CI 0.010–0.081], p value 0.01), but not with the presence of lacunes (OR 1.011 [95% CI 0.803–1.273], p value 0.92) or microbleeds (OR 1.055 [95% CI 0.896–1.242], p value 0.52).ConclusionA compound score of eMVD is associated with WMH volume. Further research is needed to expand the knowledge about the role of systemic MVD in the pathophysiology of cSVD.

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Blood pressure variability and microvascular dysfunction: the Maastricht Study.

Microvascular dysfunction (MVD) contributes to stroke, dementia, depression, retinopathy and chronic kidney disease. However, the determinants of MVD are incompletely understood. Greater blood pressure variability (BPV) may be one such determinant. We used cross-sectional data of The Maastricht Study (n = 2773, age 59.9 years; 51.9% men) to investigate whether greater very short- to mid-term BPV is associated with various MVD measures. We standardized and averaged within-visit, 24-h and 7-day BPV into a systolic and a diastolic BPV composite score. MVD measures included a composite score of MRI cerebral small vessel disease (CSVD) features (total brain parenchymal volume, white matter hyperintensity volume, lacunar infarcts and cerebral microbleeds), a composite score of flicker light-induced retinal arteriolar and venular dilation response, albuminuria, heat-induced skin hyperemia and a composite score of plasma biomarkers of MVD (sICAM-1, sVCAM-1, sE-selectin and von Willebrand Factor). We used linear regression adjusted for age, sex, glucose metabolism status, mean 24-h systolic or DBP, cardiovascular risk factors and antihypertensive medication. We found that higher systolic and diastolic BPV composite scores (per SD) were associated with higher albuminuria [higher ratio, 1.04 (95% CI 1.00-1.08) and 1.07 (1.03-1.11), respectively], but not with other measures of MVD tested. Greater systolic and diastolic BPV was associated with higher albuminuria, but not with CSVD features, flicker light-induced retinal arteriolar and venular dilation response, heat-induced skin hyperemia and plasma biomarkers of MVD. This suggests that the microvasculature of the kidneys is most vulnerable to the detrimental effects of greater BPV.

Associations of Arterial Stiffness With Cognitive Performance, and the Role of Microvascular Dysfunction: The Maastricht Study.

The mechanisms underlying cognitive impairment are incompletely understood but may include arterial stiffness and microvascular dysfunction. In the population-based Maastricht Study, we investigated the association between arterial stiffness and cognitive performance, and whether any such association was mediated by microvascular dysfunction. We included cross-sectional data of 2544 participants (age, 59.7 years; 51.0% men; 26.0% type 2 diabetes mellitus). We used carotid-femoral pulse wave velocity and carotid distensibility coefficient as measures of aortic and carotid stiffness, respectively. We calculated a composite score of microvascular dysfunction based on magnetic resonance imaging features of cerebral small vessel disease, flicker light-induced retinal arteriolar and venular dilation response, albuminuria, and plasma biomarkers of microvascular dysfunction (sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [von Willebrand factor]). Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the average of these domains. Higher aortic stiffness (per m/s) was associated with lower cognitive function (β, -0.018 SD [95% CI, -0.036 to -0.000]) independent of age, sex, education, and cardiovascular risk factors, but higher carotid stiffness was not. Higher aortic stiffness (per m/s) was associated with a higher microvascular dysfunction score (β, 0.034 SD [95% CI, 0.014 to 0.053]), and a higher microvascular dysfunction score (per SD) was associated with lower cognitive function (β, -0.089 SD [95% CI, -0.124 to -0.053]). Microvascular dysfunction significantly explained 16.2% of the total effect of aortic stiffness on cognitive function. The present study showed that aortic stiffness, but not carotid stiffness, is independently associated with worse cognitive performance, and that this association is in part explained by microvascular dysfunction.

Clinical Implications

HomeHypertensionVol. 75, No. 1Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published11 Dec 2019https://doi.org/10.1161/HYPERTENSIONAHA.119.14339Hypertension. 2020;75:2is related toImportance of Early Diagnosis in Peripartum CardiomyopathyMicrovascular Dysfunction Is Associated With Worse Cognitive PerformanceHigh Blood Pressure in Young Adult Survivors Born Extremely Preterm or Extremely Low Birthweight in the Post Surfactant EraHigh Blood Pressure in Young Adults Born Preterm (page 211)Download figureDownload PowerPointInfants who were born extremely preterm (EP; <28 weeks’ gestation) or extremely low birthweight (ELBW; <1000 g) are now surviving into adulthood in increasing numbers. In our study, young adults born EP/ELBW in the early 1990s had substantially elevated blood pressure at 25 years of age compared with controls (>2499 g at birth), with higher proportions in the hypertensive range. Importantly, blood pressure increased more in the EP/ELBW group between 18 and 25 years compared with controls. Our findings have several important clinical implications. Health care professionals, families of EP/ELBW infants, and the survivors themselves should all be aware of the increased risk for high blood pressure in those born EP/ELBW. Taking a complete perinatal history, including gestational age and birthweight, and offering blood pressure measurements, along with advocating for a healthy lifestyle, are recommended when patients born EP/ELBW present for a health check-up. An early, simple proactive approach in the timely identification and control of high blood pressure may lead to improved long-term cardiovascular outcomes in this rapidly growing at-risk population of young adults.Microvascular Damage May Impair Cognitive Function (page 237)Download figureDownload PowerPointCognitive impairment and dementia are major health problems and their prevalence rises with the aging of the population. The mechanisms underlying cognitive impairment remain, however, incompletely understood, and may include microvascular dysfunction and damage. The microvasculature is involved in the regulation of many cerebral processes, notably neurovascular coupling, cerebral autoregulation, and blood-brain barrier permeability. Impairment of these processes may lead to neuronal dysfunction and contribute to cognitive decline. However, evidence for an association between microvascular dysfunction and worse cognitive performance is limited. We therefore used cross-sectional data from the large population-based Maastricht Study to test whether microvascular dysfunction is associated with worse cognitive function. Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. The results showed an association between microvascular dysfunction and worse cognitive performance independent of a large set of potential confounders. These findings support the hypothesis that microvascular dysfunction contributes to the development of cognitive impairment and suggest that microvascular dysfunction may be a target for prevention strategies of cognitive impairment. Future longitudinal studies are needed to further evaluate the association of microvascular dysfunction and cognitive decline and dementia.Early Diagnosis and PPCM Recovery (page 91)Download figureDownload PowerPointPeripartum cardiomyopathy (PPCM) is an often severe form of cardiomyopathy diagnosed towards the end of pregnancy or in the months after delivery. Most women will recover, however, a significant percentage experience persistent cardiomyopathy. Hypertensive disorders of pregnancy (HDP) such as preeclampsia are one of the strongest risk factors for PPCM and share a common pathophysiological mechanism. The rapid resolution of angiogenic imbalance in preeclampsia may lead to faster recovery in women with HDP and PPCM but controversy remains on whether HDP predict a favorable outcome. Timing of diagnosis and race may confound this relationship, as black women are more likely to be diagnosed with HDP, less likely to recover, and more likely to be diagnosed later in the postpartum period. In this single-center study of 220 women with PPCM, patients with HDP were diagnosed earlier postpartum than patients without HDP, an effect that was most pronounced in nonblack patients. Hypertensive disorders of pregnancy were not associated with improved recovery rates. In contrast, early diagnosis (<1-month postpartum) was associated with improved recovery compared to women diagnosed later in the postpartum period. These findings were consistent among black and nonblack women. Notably, women diagnosed early had less severe LV dysfunction, which likely explains the association between early diagnosis and improved outcomes. Improving the early diagnosis of PPCM in at-risk women may improve clinical outcomes in traditionally underserved populations. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesImportance of Early Diagnosis in Peripartum CardiomyopathyJennifer Lewey, et al. Hypertension. 2020;75:91-97Microvascular Dysfunction Is Associated With Worse Cognitive PerformanceSytze P. Rensma, et al. Hypertension. 2020;75:237-245High Blood Pressure in Young Adult Survivors Born Extremely Preterm or Extremely Low Birthweight in the Post Surfactant EraAnjali Haikerwal, et al. Hypertension. 2020;75:211-217 January 2020Vol 75, Issue 1 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.119.14339PMID: 31825745 Originally publishedDecember 11, 2019 PDF download Advertisement

Microvascular Dysfunction Is Associated With Worse Cognitive Performance: The Maastricht Study.

Microvascular dysfunction may be associated with worse cognitive performance. Most previous studies did not adjust for important confounders, evaluated only individual measures of microvascular dysfunction, and showed inconsistent results. We evaluated the association between a comprehensive set of measures of microvascular dysfunction and cognitive performance in the population-based Maastricht Study. We used cross-sectional data including 3011 participants (age 59.5±8.2; 48.9% women; 26.5% type 2 diabetes mellitus [oversampled by design]). Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the sum of the scores on these 3 cognitive domains. The microvascular dysfunction score was associated with a worse cognitive function score (standardized β, -0.087 [95% CI, -0.127 to -0.047]), independent of age, education level, sex, type 2 diabetes mellitus, smoking, alcohol use, hypertension, total/HDL (high-density lipoprotein) cholesterol ratio, triglycerides, lipid-modifying medication, prior cardiovascular disease, depression and plasma biomarkers of low-grade inflammation. The fully adjusted β-coefficient of the association between the microvascular dysfunction score and the cognitive function score was equivalent to 2 (range, 1-3) years of aging for each SD higher microvascular dysfunction score. The microvascular dysfunction score was associated with worse memory and processing speed but not with worse executive function. The present study shows that microvascular dysfunction is associated with worse cognitive performance.

Aging Impairs Cerebrovascular Reactivity at Preserved Resting Cerebral Arteriolar Tone and Vascular Density in the Laboratory Rat.

The age-related (mal)adaptive modifications of the cerebral microvascular system have been implicated in cognitive impairment and worse outcomes after ischemic stroke. The magnitude of the hyperemic response to spreading depolarization (SD), a recognized principle of ischemic lesion development has also been found to be reduced by aging. Here, we set out to investigate whether the SD-coupled reactivity of the pial arterioles is subject to aging, and whether concomitant vascular rarefaction may contribute to the age-related insufficiency of the cerebral blood flow (CBF) response. CBF was assessed with laser-speckle contrast analysis (LASCA), and the tone adjustment of pial arterioles was followed with intrinsic optical signal (IOS) imaging at green light illumination through a closed cranial window created over the parietal cortex of isoflurane-anesthetized young (2 months old) and old (18 months old) male Sprague–Dawley rats. Global forebrain ischemia and later reperfusion were induced by the bilateral occlusion and later release of both common carotid arteries. SDs were elicited repeatedly with topical 1M KCl. Pial vascular density was measured in green IOS images of the brain surface, while the density and resting diameter of the cortical penetrating vasculature was estimated with micro-computed tomography of paraformaldehyde-fixed cortical samples. Whilst pial arteriolar dilation in response to SD or ischemia induction were found reduced in the old rat brain, the density and resting diameter of pial cortical vessels, and the degree of SD-related oligemia emerged as variables unaffected by age in our experiments. Spatial flow distribution analysis identified an age-related shift to a greater representation of higher flow ranges in the reperfused cortex. According to our data, impairment of functional arteriolar dilation, at preserved vascular density and resting vascular tone, may be implicated in the age-related deficit of the CBF response to SD, and possibly in the reduced efficacy of neurovascular coupling in the aging brain. SD has been recognized as a potent pathophysiological contributor to ischemic lesion expansion, in part because of the insufficiency of the associated CBF response. Therefore, the age-related impairment of cerebral vasoreactivity as shown here is suggested to contribute to the age-related acceleration of ischemic lesion development.

Serum Phosphate and Microvascular Function in a Population-Based Cohort.

Higher serum phosphate is associated with cardiovascular events and all-cause mortality. Explanations of this association have focused on large vessel calcification and stiffness. Studies suggest that a higher serum phosphate induces microvascular dysfunction, but relationships in humans with direct measures of microvascular function are lacking. We performed a cross-sectional analysis of 3189 community-living participants that underwent skin capillaroscopy, laser-Doppler flowmetry, and flicker light-induced retinal vessel responses. We used linear regression to assess the association between serum phosphate and each microvascular outcome. The primary outcome was skin capillary recruitment during postocclusive peak reactive hyperemia by capillaroscopy. Secondary outcomes included capillary recruitment during venous congestion, heat-induced skin hyperemic response, flicker light-induced retinal arteriolar, and venular dilation. The mean age of the cohort was 59±8 years, 48% were women, 7% had an eGFR <60 ml/min per 1.73 m2, and the mean serum phosphate concentration was 3.2±0.5 mg/dl. A 1 mg/dl higher serum phosphate was independently associated with a 5.0% lower postocclusive capillary recruitment (95% CI, -10.0% to -0.1%). Results were similar for capillary recruitment with venous congestion (-4.5%; 95% CI, -9.8% to 0.7%). A 1 mg/dl higher serum phosphate was also independently associated with a 0.23% lower retinal venular dilation in response to flicker light (95% CI, -0.44% to -0.02%). A higher serum phosphate was not associated with change in flicker light-induced retinal arteriolar dilation or heat-induced skin hyperemic response, however a higher serum phosphate was associated with a lower heat-induced skin hyperemic response among men (-149% [95% CI, -260 to -38] per 1 mg/dl higher serum phosphate) but not women (P interaction, 0.01). Higher serum phosphate concentrations, even within the normal range, are associated with microvascular dysfunction in community-living individuals. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_20_CJN02610319.mp3.

Dynamic Responses in Retinal Vessel Caliber With Flicker Light Stimulation and Risk of Diabetic Retinopathy and Its Progression.

This study investigated the associations between the responses of retinal vessels to flickering light and the incidence and progression of diabetic retinopathy (DR). A prospective cohort study of adult subjects with diabetes mellitus. The dynamic vessel analyser (DVA) was used to measure retinal vascular dilatation in response to diffuse illuminance flicker. Diabetic retinopathy was graded from retinal photography at baseline and at 1 year. Incident DR and two-step change in DR were analyzed. There were 276 subjects in total, with a mean age of 59.8 ± 8.9 years. The majority were male (73%) and the mean glycated hemoglobin A1c (HbA1c) level and mean duration of diabetes were 7.7 ± 1.4% and 14.0 ± 10.5 years, respectively. After adjustments for age, sex, smoking, duration of diabetes, HbA1c, hypertension, and hyperlipidemia, the responses of retinal arterioles to flicker stimulation were lower in subjects with incident DR (P = 0.048). Subjects with greater arteriolar dilatory responses were less likely to have DR progression (odds ratio [OR] 1.85, [95% confidence interval [CI] 1.33-2.56], P = 0.012, per SD decrease). Subjects with greater venular dilatory responses were also less likely to have DR progression (OR 1.89, [95% CI 1.35-2.63], P = 0.003, per SD decrease). There were no significant associations between arteriolar or venular dilation response and incident proliferative DR (PDR) and DR regression. Reduced retinal arteriolar and venular dilatory responses to flickering light are associated with risk of DR progression at 1 year in adult patients with diabetes.

Homocysteine Inhibition of Endothelium-Dependent Nitric Oxide-Mediated Dilation of Porcine Retinal Arterioles via Enhanced Superoxide Production

Elevated plasma concentration of homocysteine, a sulfur-containing amino acid, is an emerging risk factor for cardiovascular diseases. Recent epidemiologic studies have confirmed that elevated homocysteine levels are associated with ocular vascular diseases; however, the direct effect of homocysteine on ocular microvascular reactivity remains unknown. We investigated whether homocysteine affects endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles and whether oxidative stress and distinct protein kinase signaling pathways are involved in the homocysteine-mediated effect. Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Diameter changes were recorded using videomicroscopy techniques. Intraluminal treatment with homocysteine (1 mM, 180 minutes) significantly attenuated arteriolar dilation in response to the endothelium-dependent NO-mediated agonists bradykinin and A23187 but not in response to the endothelium-independent NO donor sodium nitroprusside. In the presence of the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), the nicotinamide adenine dinucleotide phosphate-oxidase (NAD(P)H oxidase inhibitor apocynin, p38 kinase inhibitor SB203580, and peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone, the detrimental effect of homocysteine on bradykinin-induced dilation was prevented; however, neither the xanthine oxidase inhibitor allopurinol, the JNK inhibitor SP600125, or pioglitazone with PPAR-γ inhibitor GW9662 had that effect. Homocysteine inhibits endothelium-dependent NO-mediated dilation in the retinal arterioles by producing superoxide from NAD(P)H oxidase, which appears to be linked with p38 kinase. By impairing endothelium-dependent NO-mediated vasoreactivity, homocysteine potentially facilitates development of retinal vascular diseases. In addition, pioglitazone can prevent homocysteine-induced endothelial dysfunction possibly by activating PPAR-γ.

Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate

In newborn pigs, vasodilation of pial arterioles in response to glutamate is mediated via carbon monoxide (CO), a gaseous messenger endogenously produced from heme degradation by a heme oxygenase (HO)-catalyzed reaction. We addressed the hypothesis that ionotropic glutamate receptors (iGluRs), including N-methyl-D-aspartic acid (NMDA)- and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA)/kainate-type receptors, expressed in cortical astrocytes mediate glutamate-induced astrocyte HO activation that leads to cerebral vasodilation. Acute vasoactive effects of topical iGluR agonists were determined by intravital microscopy using closed cranial windows in anesthetized newborn pigs. iGluR agonists, including NMDA, (±)1-aminocyclopentane-cis-1,3-dicarboxylic acid (cis-ACPD), AMPA, and kainate, produced pial arteriolar dilation. Topical L-2-aminoadipic acid, a gliotoxin that selectively disrupts glia limitans, reduced vasodilation caused by iGluR agonists, but not by hypercapnia, bradykinin, or sodium nitroprusside. In freshly isolated and cultured cortical astrocytes constitutively expressing HO-2, iGluR agonists NMDA, cis-ACPD, AMPA, and kainate rapidly increased CO production two- to threefold. Astrocytes overexpressing inducible HO-1 had high baseline CO but were less sensitive to glutamate stimulation of CO production when compared with HO-2-expressing astrocytes. Glutamate-induced astrocyte HO-2-mediated CO production was inhibited by either the NMDA receptor antagonist (R)-3C4HPG or the AMPA/kainate receptor antagonist DNQX. Accordingly, either antagonist abolished pial arteriolar dilation in response to glutamate, NMDA, and AMPA, indicating functional interaction among various subtypes of astrocytic iGluRs in response to glutamate stimulation. Overall, these data indicate that the astrocyte component of the neurovascular unit is responsible for the vasodilation response of pial arterioles to topically applied glutamate via iGluRs that are functionally linked to activation of constitutive HO in newborn piglets.

Nanoparticle inhalation alters systemic arteriolar vasoreactivity through sympathetic and cyclooxygenase-mediated pathways

The widespread increase in the production and use of nanomaterials has increased the potential for nanoparticle exposure; however, the biological effects of nanoparticle inhalation are poorly understood. Rats were exposed to nanosized titanium dioxide aerosols (10 μg lung burden); at 24 h post-exposure, the spinotrapezius muscle was prepared for intravital microscopy. Nanoparticle exposure did not alter perivascular nerve stimulation (PVNS)-induced arteriolar constriction under normal conditions; however, adrenergic receptor inhibition revealed a more robust effect. Nanoparticle inhalation reduced arteriolar dilation in response to active hyperaemia (AH). In both PVNS and AH experiments, nitric oxide synthase (NOS) inhibition affected only controls. Whereas cyclooxygenase (COX) inhibition only attenuated AH-induced arteriolar dilation in nanoparticle-exposed animals. This group displayed an enhanced U46619 constriction and attenuated iloprost-induced dilation. Collectively, these studies indicate that nanoparticle exposure reduces microvascular NO bioavailability and alters COX-mediated vasoreactivity. Furthermore, the enhanced adrenergic receptor sensitivity suggests an augmented sympathetic responsiveness.

Dynamic retinal vessel response to flicker in obesity: A methodological approach

Obesity and related metabolic disorders affect vascular endothelial function. The use of the Dynamic Vessel Analyzer (DVA) represents a modern methodological approach to analyze vascular function in the retinal microcirculation. Whether the dynamic reaction to flicker stimulation in retinal vessels is altered in obese subjects is investigated. Retinal vessel reactions to flicker stimulation were examined by DVA in 46 obese individuals (49.6 ± 10.0 years) and 46 age- and gender-matched healthy controls. The clinical examination included anthropometry, blood pressure measurements and blood sampling. Mean maximal arteriolar dilation in response to flicker was reduced in the obese group (3.2 ± 1.8%) compared to controls (4.1 ± 2.0%, p < 0.05) and the time to maximal arteriolar dilation was prolonged (18.0 ± 9.4 s vs. 14.6 ± 3.8 s, p = 0.03). In addition, mean maximal venular dilation was reduced in obese subjects (3.9 ± 1.7% vs. 4.7 ± 1.8%, p < 0.05). Among the microvascular parameters, the most significant correlation with waist circumference was found for the “area under the reaction curve 50–80 s after stimulation” in arterioles (r = − 0.40; p < 0.001). Functional retinal arteriolar reactivity to flicker stimulation differs between obese and healthy lean subjects. Time course analysis of retinal vessel response and its quantitative parameters can comprehensively characterize alterations of retinal vessel reactivity in metabolic disease.

The Soluble Epoxide Hydrolase Inhibitor AR9281 Decreases Blood Pressure, Ameliorates Renal Injury and Improves Vascular Function in Hypertension.

Soluble epoxide hydrolase inhibitors (sEHIs) are demonstrating promise as potential pharmaceutical agents for the treatment of cardiovascular disease, diabetes, inflammation, and kidney disease. The present study determined the ability of a first-in-class sEHI, AR9281, to decrease blood pressure, improve vascular function, and decrease renal inflammation and injury in angiotensin hypertension. Rats were infused with angiotensin and AR9281 was given orally during the 14-day infusion period. Systolic blood pressure averaged 180 ± 5 mmHg in vehicle treated and AR9281 treatment significantly lowered blood pressure to 142 ± 7 mmHg in angiotensin hypertension. Histological analysis demonstrated decreased injury to the juxtamedullary glomeruli. Renal expression of inflammatory genes was increased in angiotensin hypertension and two weeks of AR9281 treatment decreased this index of renal inflammation. Vascular function in angiotensin hypertension was also improved by AR9281 treatment. Decreased afferent arteriolar and mesenteric resistance endothelial dependent dilator responses were ameliorated by AR9281 treatment of angiotensin hypertensive rats. These data demonstrate that the first-in-class sEHI, AR9281, lowers blood pressure, improves vascular function and reduces renal damage in angiotensin hypertension.

The role of adenosine in hypercarbic hyperemia: in vivo and in vitro studies in adenosine 2A receptor knockout and wild-type mice

The authors tested the hypothesis that adenosine, acting through the A(2A) receptor, is not involved in hypercarbic hyperemia by assessing the effects of increased PaCO(2) on cerebral blood flow (CBF) in vivo in wild-type and A(2A) receptor knockout mice. In addition, they evaluated the effect of abluminal pH changes in vitro on the diameter of isolated perfused penetrating arterioles harvested from wild-type and A(2A) receptor knockout mice. The authors evaluated in a blinded fashion the CBF response during transient (60-second) hypercapnic (7% CO(2)) hypercarbia in anesthetized, ventilated C57Bl/6 wild-type and adenosine A(2A) receptor knockout mice. They also evaluated the hypercarbic response in the absence and presence of the nonselective and selective adenosine antagonists. Cerebral blood flow was measured using laser Doppler flowmetry. There were no differences between the CBF responses to hypercarbia in the wild-type and the knockout mice. Moreover, the hypercarbic hyperemia response was not affected by the adenosine receptor antagonists. The authors also tested the response to alteration in abluminal pH in isolated perfused, pressurized, penetrating arterioles (average diameter 63.3 +/- 3.6 microm) harvested from wild-type (6 mice) and knockout (5 mice) animals. Arteriolar dilation in response to a decrease in abluminal pH, simulating the change in vivo during hypercarbia, was similar in wild-type (15.9 +/- 2.6%) and A(2A) receptor knockout (17.7 +/- 1.3%) mice. With abluminal application of CGS 21680 (10(-6) M), an A(2A) receptor agonist, wild-type arterioles dilated in an expected manner (9.8 +/- 0.7%), whereas A(2A) receptor knockout vessels had minimal response. The results of the in vivo and in vitro studies in wild-type and A(2A) receptor knockout mice support the authors' hypothesis that hypercarbic vasodilation does not involve an adenosine A(2A) receptor-related mechanism.

Modulation of Vascular O2 Responses by Cytochrome 450‐4A ω‐Hydroxylase Metabolites In Dahl Salt‐Sensitive Rats

This study evaluated the role of the 20-HETE/cytochrome P450-4A omega-hydroxylase (CYP450-4A) system in microvascular regulation in the skeletal muscle circulation following short-term (three-day) exposure to a high-salt (HS) diet in Dahl salt-sensitive (SS) rats. The effects of inhibiting CYP450-4A on resting diameter, O(2)-induced constriction, and vasodilator responses to acetylcholine (ACh) and the nitric oxide (NO) donor, sodium nitroprusside (SNP), were evaluated in cremasteric arterioles of SS rats fed a low- (LS; 0.4% NaCl) or high-salt (HS; 4% NaCl) diet for three days. The HS diet upregulated CYP450-4A mRNA expression and led to an enhanced constriction of arterioles in response to elevated PO(2) in SS rats, which could be blocked by inhibiting CYP450-4A enzymes with dibromododecenyl methylsulfimide (DDMS). DDMS also inhibited resting tone significantly in SS rats fed the HS, but not the LS, diet, despite similar resting diameters and active tone in the two groups. Arteriolar dilations in response to ACh and SNP were similar in SS rats fed the LS vs. the HS diet and were unaffected by DDMS. These findings suggest that CYP450-4A enzymes contribute to resting tone and to an enhanced response to elevated PO(2) in arterioles of Dahl-SS rats fed the HS diet.

Pulmonary Nanoparticle Exposure Disrupts Systemic Microvascular Nitric Oxide Signaling

We have shown that pulmonary nanoparticle exposure impairs endothelium dependent dilation in systemic arterioles. However, the mechanism(s) through which this effect occurs is/are unclear. The purpose of this study was to identify alterations in the production of reactive species and endogenous nitric oxide (NO) after nanoparticle exposure, and determine the relative contribution of hemoproteins and oxidative enzymes in this process. Sprague-Dawley rats were exposed to fine TiO2 (primary particle diameter approximately 1 microm) and TiO2 nanoparticles (primary particle diameter approximately 21 nm) via aerosol inhalation at depositions of 4-90 microg per rat. As in previous intravital experiments in the spinotrapezius muscle, dose-dependent arteriolar dilations were produced by intraluminal infusions of the calcium ionophore A23187. Nanoparticle exposure robustly attenuated these endothelium-dependent responses. However, this attenuation was not due to altered microvascular smooth muscle NO sensitivity because nanoparticle exposure did not alter arteriolar dilations in response to local sodium nitroprusside iontophoresis. Nanoparticle exposure significantly increased microvascular oxidative stress by approximately 60%, and also elevated nitrosative stress fourfold. These reactive stresses coincided with a decreased NO production in a particle deposition dose-dependent manner. Radical scavenging, or inhibition of either myeloperoxidase or nicotinamide adenine dinucleotide phosphate oxidase (reduced) oxidase partially restored NO production as well as normal microvascular function. These results indicate that in conjunction with microvascular dysfunction, nanoparticle exposure also decreases NO bioavailability through at least two functionally distinct mechanisms that may mutually increase local reactive species.