Responses Of Carotid Arteries Research Articles

Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling.

Restenosis after angioplasty is caused usually by neointima formation characterized by aberrant vascular smooth muscle cell (VSMC) dedifferentiation. Myeloid-derived growth factor (MYDGF), secreted from bone marrow-derived monocytes and macrophages, has been found to have cardioprotective effects. In this study we investigated the effect of MYDGF to postinjury neointimal formation and the underlying mechanisms. Rat carotid arteries balloon-injured model was established. We found that plasma MYDGF content and the level of MYDGF in injured arteries were significantly decreased after balloon injury. Local application of exogenous MYDGF (50 μg/mL) around the injured vessel during balloon injury markedly ameliorated the development of neointimal formation evidenced by relieving the narrow endovascular diameter, improving hemodynamics, and reducing collagen deposition. In addition, local application of MYDGF inhibited VSMC dedifferentiation, which was proved by reversing the elevated levels of osteopontin (OPN) protein and decreased levels of α-smooth muscle actin (α-SMA) in the left carotid arteries. We showed that PDGF-BB (30 ng/mL) stimulated VSMC proliferation, migration and dedifferentiation in vitro; pretreatment with MYDGF (50-200 ng/mL) concentration-dependently eliminated PDGF-BB-induced cell proliferation, migration and dedifferentiation. Molecular docking revealed that MYDGF had the potential to bind with sphingosine-1-phosphate receptor 2 (S1PR2), which was confirmed by SPR assay and Co-IP analysis. Pretreatment with CCG-1423 (Rho signaling inhibitor), JTE-013 (S1PR2 antagonist) or Ripasudil (ROCK inhibitor) circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching through inhibiting S1PR2 or its downstream RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling. In summary, this study proves that MYDGF relieves neointimal formation of carotid arteries in response to balloon injury in rats, and suppresses VSMC dedifferentiation induced by PDGF-BB via S1PR2-RhoA-G/F-actin-MRTF-A signaling pathway. In addition, our results provide evidence for cross talk between bone marrow and vasculature.

Probing the crosslinking independent roles of tissue transglutaminase in vascular aging using a novel transamidation‐deficient TGM2‐C277S mouse model

IntroductionTissue transglutaminase (TG2) is a multifunctional protein of the transglutaminase family with putative transamidation‐independent functions in aging associated vascular stiffening and dysfunction. The development of preclinical models is critical to fully understand the physiological relevance of transamidation independent functions of TG2 and to identify the specific function of TG2 for therapeutic targeting. Therefore, In this study we harnessed the CRISPR‐Cas9 gene editing technology to introduce a mutation at the active site cysteine (C277) in the mouse TGM2 gene.Methods and resultsWe investigated the contributions of the transamidation‐dependent vs. transamidaiton‐independent functions of TG2 in vascular aging using TGM2‐C277S mice, littermate WT mice, and age‐matched TG2−/− mice. Heterozygous and homozygous TGM2‐C277S mice were phenotypically normal and were born at the expected Mendelian frequency. TG2 protein abundance was similar to wild‐type (WT) in the TGM2‐C277S mutant mice in the liver, lung, heart, aorta, and kidney. GTP binding, and interactions with fibronectin and integrin beta1 were preserved in the TG2‐C277S mouse protein. Transglutaminase function was absent in the TG2 protein from TGM2‐C277S mice when compared with wild‐type (WT) littermates. Loss of transamidation function resulted in a marked loss in serotonin induced vasoconstriction and in vitro remodeling of the carotid artery in response to chronic vasoconstriction. On the other hand, cell adhesion and proliferation were comparable to that of WT in the vascular smooth muscle cells from TGM2‐C277S but not in those from TG2−/− mice. Vascular stiffness increased with age in WT mice, as measured by pulse wave velocity, tensile testing, and pressure myography. TGM2‐C277S mice were markedly protected from age‐associated vascular stiffening, but not to the same extent as TG2−/− mice.ConclusionsTogether, these studies show that the TGM2‐C277S mice ubiquitously express a TG2 protein that lacks transamidation function and retains its other functions and can be used a tool for in vivo studies to examine the transamidation‐independent roles of TG2 in physiology and pathophysiology. While TG2‐mediated ECM crosslinking and VSMC dysfunction, both propagate vascular stiffening in aging, the transamidation function is the primary shareholder in aging associated mechanical decline of the large vessels.Support or Funding InformationThis work was funded by a StAAR Investigator Award (to LS) and a MedImmune Research Funds Award (to LS).

Pulse Pressure and Carotid Artery Doppler Velocimetry as Indicators of Maternal Volume Status: A Prospective Cohort Study.

Narrow pulse pressure has been demonstrated to indicate low central volume status. In critically ill patients, volume status can be qualitatively evaluated using Doppler velocimetry to assess hemodynamic changes in the carotid artery in response to autotransfusion with passive leg raise (PLR). Neither parameter has been prospectively evaluated in an obstetric population. The objective of this study was to determine if pulse pressure could predict the response to autotransfusion using carotid artery Doppler in healthy intrapartum women. We hypothesized that the carotid artery Doppler response to PLR would be greater in women with a narrow pulse pressure, indicating relative hypovolemia. Intrapartum women with singleton gestations ≥35 weeks without acute or chronic medical conditions were recruited to this prospective cohort study. Participants were grouped by admission pulse pressure as <45 mm Hg (narrow) or ≥50 mm Hg (normal). Maternal carotid artery Doppler assessment was then performed in all patients before and after PLR using a standard technique where carotid blood flow (mL/min) = π × (carotid artery diameter/2) × (velocity time integral) × (60 seconds). The velocity time integral was calculated from the Doppler waveform. The primary outcome was the change in the carotid Doppler parameters (carotid artery diameter, velocity time integral, and carotid blood flow) after PLR. Outcomes were compared between study groups with univariable and multivariable analyses with adjustment for potential confounding factors. Thirty-three women consented to participation, including 18 in the narrow and 15 in the normal pulse pressure groups (mean and standard deviation initial pulse pressure, 38.3 ± 4.4 vs 57.3 ± 4.1 mm Hg). The 2 groups demonstrated similar characteristics except for initial pulse pressure, systolic and diastolic blood pressure, and race. In response to PLR, the narrow pulse pressure group had a significantly greater increase in carotid artery diameter (0.08 vs 0.02 cm; standardized difference, 2.0; 95% confidence interval [CI], 1.16-2.84), carotid blood flow (79.4 vs 16.0 mL/min; standardized difference, 2.23; 95% CI, 1.36-3.10), and percent change in carotid blood flow (47.5% vs 8.7%; standardized difference, 2.52; 95% CI, 1.60-3.43) compared with the normal pulse pressure group. In multivariable analysis with adjustment for potential confounding factors, women with narrow admission pulse pressure had a significantly larger carotid diameter (0.66 vs 0.62 cm; P < .0001) and greater carotid flow (246.7 vs 219.3 cm/s; P = .001) after PLR compared to women with a normal pulse pressure. Initial pulse pressure was strongly correlated with the change in carotid flow after PLR (r = 0.60; P < .0001). The hemodynamic response of the carotid artery to autotransfusion after PLR is significantly greater in women with narrow pulse pressure. Pulse pressure correlates with the physiological response to autotransfusion and provides a qualitative indication of intravascular volume in term and near-term pregnant women.

The Effect of Resveratrol on Reducing Neointimal Growth after Femoral Artery Injury in AMPKα2 Knockout Mice Given High-Fat Diet

The rates of restenosis after percutaneous transluminal angioplasty are higher in diabetic than nondiabetic patients. Insulin is protective against restenosis, but these effects are diminished in the case of insulin resistance, which develops with high fat diet (HFD). Therefore, it makes sense to use an insulin-sensitizing compound which also has vasculoprotective effects such as resveratrol. Resveratrol is a phenolic compound found in plant tissues such as the skin of grapes, and has been hypothesized to account for the lower rates of cardiovascular disease among countries with high wine consumption. We have shown that resveratrol decreases neointimal formation in both mouse and rat models of arterial injury, and also that these effects are exerted through eNOS (endothelial nitric oxide synthase). We hypothesized that resveratrol acts though Sirt1, a NAD+-dependent deacetylase, to activate eNOS and decrease neointimal formation, but did not see any difference between neointimal growth of control and Sirt1-/- mice given HFD. AMPK (AMP-activated protein kinase) is an energy sensor which also protects against neointimal hyperplasia in the vasculature via directly activating eNOS and inhibiting the migration of vascular smooth muscle cells. Knocking out the α2 subunit of AMPK in particular has been shown to increase neointimal growth in mouse carotid artery in response to injury. We investigated the effect of resveratrol on neointimal growth after femoral arterial injury of wild type and AMPKα2 knock-out mice given HFD. Resveratrol was given at 0.0375% in the diet two days after wire injury. After 28 days, arteries were harvested and histomorphometric analysis was performed on the cross-sections. We found that neointimal growth was significantly higher in AMPKα2 knock-out mice given resveratrol compared to wild type mice given resveratrol (p&amp;lt;0.05). These results suggest that the vasculoprotective effects of resveratrol are mediated through AMPK. Disclosure L. Zhou: None. J. Guo: None. H. Zhang: None. S. Heximer: None. A. Giacca: None.

Cardiovascular Effects of Endothelial‐Specific Interference with PPARγ Activity in Offspring Born from AVP‐induced Preeclamptic Pregnancies

PPARγ is a ligand‐activated transcription factor known to regulate metabolic and vascular function. Mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant‐negative (DN) PPARγ driven by an endothelium‐specific promoter (E‐DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular and metabolic risk to offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. C57BL/6J dams were bred with E‐DN sires, and symptoms of PE were induced by the infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. We assessed phenotypes of PE first in pregnant dams, and then in offspring as adults. Compared to saline infusion (SAL), AVP elevated maternal blood pressure (SBP: 116±3 vs 107±3, p&lt;0.05) at gestational day (GD) 14–15 and urine protein (70±6 vs 27±4 mg/mL, p&lt;0.05) at GD17. Offspring from these pregnancies were phenotyped in adulthood to assess cardiovascular function. Data were stratified to sex, genotype, and maternal exposure to AVP vs SAL. Systolic blood pressure in adult male and female offspring born to AVP‐infused pregnancies was similar to mice born to SAL‐infused control pregnancies. Urinary protein levels were significantly elevated in both male (58±13 vs 32±5 mg/ml, p&lt;0.05) and female (38±3 vs 25±2 mg/ml, p&lt;0.05) adult E‐DN born to PE pregnancies compared to E‐DN controls born from SAL pregnancies. At 20 weeks of age, vasorelaxation responses to acetylcholine (ACh) were not different in offspring exposed to PE compared to mice born from SAL pregnancies. Interestingly, in response to a sub‐pressor dose of Angiotensin II (120 ng/kg/hr for 14 days), a known cardiovascular stressor, adult male E‐DN born to PE pregnancies, but not NT mice exhibited significant impairment in ACh‐induced relaxation in carotid artery (maximum relaxation at 30 μM ACh: 69±4 vs 86±3, p&lt;0.05) and basilar artery (maximum relaxation at 100 μM ACh: 19±7 vs 51±15, p&lt;0.05). Male E‐DN exposed to PE also showed a trend for endothelial dysfunction in carotid artery and basilar artery when compared to sex‐matched E‐DN born from control pregnancies (carotid: max relaxation at 30 μM ACh: 69±4 vs 86±4; basilar: max relaxation at 100 μM ACh: 19±7 vs 64±14). Further, adult female E‐DN exposed to PE also exhibited a trend for impaired endothelial function in carotid artery in response to AngII administration compared to NT controls (Maximum relaxation at 30 μM ACh: 56±12 vs 72±5). No differences in relaxation responses to sodium nitroprusside were observed. These data highlight the impact of in utero exposure to elevated AVP upon cardiovascular function in the mother, and the adverse cardiovascular consequences of PE upon offspring. Moreover, our data suggests that interference with endothelial PPARγ in pups born from AVP‐infused PE pregnancies increases the risk for endothelial dysfunction upon exposure to a cardiovascular stressor in adulthood.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Blunted shear-mediated dilation of the internal but not common carotid artery in response to lower body negative pressure

Shear-mediated dilation in peripheral conduit arteries is blunted with sympathetic nervous system (SNS) activation; however, the effect of SNS activation on shear-mediated dilation in carotid arteries is unknown. We hypothesized that SNS activation reduces shear-mediated dilation in common and internal carotid arteries (CCA and ICA, respectively), and this attenuation is greater in the ICA compared with the CCA. Shear-mediated dilation in the CCA and ICA were measured in nine healthy men (24 ± 1 yr) with and without SNS activation. Shear-mediated dilation was induced by 3 min of hypercapnia (end-tidal partial pressure of carbon dioxide +10 mmHg from individual baseline); SNS activity was increased with lower body negative pressure (LBNP; -20 mmHg). CCA and ICA measurements were made using Doppler ultrasound during hypercapnia with (LBNP) or without (Control) SNS activation. LBNP trials began with 5 min of LBNP with subjects breathing hypercapnic gas during the final 3 min. Shear-mediated dilation was calculated as the percent rise in peak diameter from baseline diameter. Sympathetic activation attenuated shear-mediated dilation in the ICA (Control vs. LBNP, 5.5 ± 0.7 vs. 1.8 ± 0.4%, P < 0.01), but not in the CCA (5.1 ± 1.2 vs. 4.2 ± 1.0%, P = 0.31). Moreover, absolute reduction in shear-mediated dilation via SNS activation was greater in the ICA than the CCA (-3.6 ± 0.7 vs. -0.9 ± 0.8%, P = 0.02). Our data indicate that shear-mediated dilation is attenuated during LBNP to a greater extent in the ICA compared with the CCA. These results potentially provide insight into the role of SNS activation on cerebral perfusion, as the ICA is a key supplier of blood to the brain. NEW & NOTEWORTHY We explored the effect of acute sympathetic nervous system (SNS) activation on shear-mediated dilation in the common and internal carotid arteries (CCA and ICA, respectively) in young healthy men. Our data demonstrate that hypercapnia-induced vasodilation of the ICA is attenuated during lower body negative pressure to a greater extent than the CCA. These data may provide novel information related to the role of SNS activation on cerebral perfusion in humans.

Control of coagulation by the RhoA pathway and the exchange factor Arhgef1

Activation of the thrombin receptors, called PAR, leads to a remodeling of the actin cytoskeleton depending on the small G proteins of the Rho family. The main one, RhoA, controls platelet contractility. The Arhgef1 nucleotide exchange factor, responsible for the activation of RhoA, is not well known. Our goal is to identify the role of Arhgef1 in platelet activity and thrombin generation in response to thrombin-activated PAR receptors. Thrombin generation, platelet activation and aggregation are measured by fluorimetry, flow cytometry, and turbidimetry in the blood of Arhgef1+/+ and Arhgef1−/− mice. The formation of a thrombus in the carotid artery in response to the local application of FeCl3, is followed by Echo-Doppler. In response to thrombin, aggregation of washed platelets and intracellular calcium are similar in Arhgef1−/− and Arhgef1+/+ mice. However, the secretion of alpha granules, exposure of phosphatidylserine and release of microparticles associated with platelet activation are decreased compared to Arhgef1+/+ mice. The generation of whole blood thrombin was significantly reduced (25%) in Arhgef1−/− mice compared to Arhgef1+/+. These changes result in an increase in the time of an occlusive thrombus occurrence induced by FeCl3 in the carotid artery. Our results show the involvement of the platelet RhoA pathway in the self-amplification of thrombin generation by a mechanism dependent on Arhgef1 and PAR receptors. Changes in the distribution of membrane phospholipids suggest that this pathway could participate in the deleterious effects of thrombin in atherothrombosis.

Differential impact of water immersion on arterial blood flow and shear stress in the carotid and brachial arteries of humans.

Arterial shear stress is a potent stimulus to vascular adaptation in humans. Typically, increases in retrograde shear have been found to acutely impair vascular function while increases in antegrade shear enhance function. We hypothesized that blood flow and shear stress through the brachial and carotid arteries would change in a similar manner in response to water immersion, an intervention which modifies hemodynamics. Nine healthy young male subjects were recruited to undergo controlled water immersion in a standing upright position to the level of the right atrium in 30°C water. Diameters were continuously and simultaneously recorded in the brachial and common carotid arteries along with mean arterial pressure (MAP), cardiac output (CO), and heart rate before, during, and after 10 min of immersion. MAP and CO increased during water immersion (baseline vs. 8–10 min; 80 ± 9 vs. 91 ± 12 mmHg; and 4.8 ± 0.7 vs. 5.1 ± 0.6 L/min, P < 0.01 and P < 0.05, respectively). We observed a differential regulation of flow and shear stress patterns in the brachial and carotid arteries in response to water immersion; brachial conductance decreased markedly in response to immersion (1.25 ± 0.56 vs. 0.57 ± 0.30 mL.min/mmHg, P < 0.05), whereas it was unaltered in the carotid artery (5.82 ± 2.14 vs. 5.60 ± 1.59). Our findings indicate that adaptations to systemic stimuli and arterial adaptation may be vessel bed specific in humans, highlighting the need to assess multiple vascular sites in future studies.

Endothelial Ephrin‐B2 is Essential for Arterial Vasodilation in Mice

The cell surface protein ephrin-B2 is expressed in arterial and not venous ECs throughout development and adulthood. Endothelial ephrin-B2 is required for vascular development and angiogenesis, but its role in established arteries is currently unknown. We investigated the physiological role of ephrin-B2 signaling in adult endothelium. We generated adult conditional knockout mice lacking the Efnb2 gene specifically in ECs and evaluated the vasodilation responses to blood flow increase and ACh in the cremaster muscle preparation by intravital microscope and in carotid artery by in vivo ultrasound. We found that the Efnb2 conditional knockout mice were defective in acute arterial dilation. Vasodilation was impaired in cremaster arterioles in response to either increased flow or ACh, and in the carotid arteries in response to increased flow. Levels of cGMP, an effector of NO, were diminished in mutant arteries following ACh stimulation. GSNO, a donor for the vasodilator NO, alleviated the vasodilatory defects in the mutants. Immunostaining showed that a subset of ephrin-B2 proteins colocalized with caveolin-1, a negative regulator of eNOS. Our data suggest that endothelial ephrin-B2 is required for endothelial-dependent arterial dilation and NO signaling in adult endothelium.

Abstract 27: Dok-1 Negatively Regulates Integrin aIIbß3 Outside-in Signaling and Inhibits Thrombosis

Background Platelet agonists activate integrin αIIbβ3 to allow the binding of soluble fibrinogen (a process known as inside-out signaling). Subsequent platelet aggregation leads to αIIbβ3 outside-in signaling, which results in tyrosine phosphorylation of β3 and other proteins, cytoskeletal reorganization, and platelet spreading. It has been reported that the adapter protein Dok-1 binds to the cytoplasmic tail of β3 and inhibits αIIbβ3 activation, but the specific role of Dok-1 in regulating inside-out or outside-in platelet signaling remains undefined. Methods We assessed the effects of Dok-1 on platelet signaling and thrombosis in Dok-1 null (Dok-1-/-) mice. Inside-out signaling was assessed by measuring αIIbβ3 activation (using the JON/A antibody) and fibrinogen binding by flow cytometry after stimulation of platelets with thrombin, ADP, and/or the thromboxane A2 receptor agonist U46619. Outside-in signaling was examined by measuring platelet spreading and clot retraction. Tail-transection bleeding time and susceptibility to thrombotic occlusion of the carotid artery in response to photochemical injury (rose bengal) were also measured. Results No significant differences in JON/A or fibrinogen binding were detected between wild-type (Dok-1+/+) and Dok-1-/- platelets, suggesting that Dok-1 does not regulate inside-out signaling. In contrast, Dok-1-/- platelets exhibited increased clot retraction and enhanced spreading on fibrinogen upon thrombin stimulation compared to Dok-1+/+ platelets (P&lt;0.05), suggesting that Dok-1 negatively regulates outside-in signaling. Compared with Dok-1+/+ mice, Dok-1-/- mice had shorter bleeding times (181±168 vs. 379±193 seconds; P&lt;0.001) and Dok-1-/- mice had shorter times to stable occlusion times of the carotid artery after photochemical injury compared with Dok-1+/+ mice (16.4±6.1 vs. 25.0±8.1 minutes; P&lt;0.05). Conclusions The adaptor protein Dok-1 functions to negatively regulate integrin αIIbβ3 outside-in signaling. Deficiency of Dok-1 results in a prothrombotic phenotype, with shorten bleeding times and enhanced arterial thrombosis.

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

BackgroundRecently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms.Methods and FindingsOtsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs.ConclusionsSitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes.

Differential effects of trimetazidine on vascular smooth muscle cell and endothelial cell in response to carotid artery balloon injury in diabetic rats

BackgroundTreatment with trimetazidine (TMZ), 1-[2,3,4-trimethoxybenzyl] piperazine, dihydrochloride, improves cardiac function and ameliorates endothelial dysfunction. However, its potential efficacy against restenosis after balloon injury has not been addressed. We investigated the effect of TMZ on reducing the occurrence of restenosis in the carotid artery in response to balloon injury and explored potential mechanisms for the effects. Material and methodsStreptozotocin (40mg/kg)-injected Sprague–Dawley rats and Otsuka Long–Evans Tokushima Fatty rats were used for type 1 and type 2 diabetes models, respectively. Both types of rats were divided into three groups: control and TMZ treatment 10 and 20mg/kg per day (n=10 per group). TMZ or normal saline was given orally from 2weeks before to 2weeks after carotid injury. ResultsFour weeks of TMZ treatment resulted in a significant and dose-dependent reduction in the intima-media ratio in diabetic rats. This effect was accompanied by decreased proliferation of vascular smooth muscle cells (VSMCs) and accelerated re-endothelialization after carotid balloon injury. In vitro study with VSMCs decreased proliferation and migration, while human umbilical vein endothelial cells (HUVECs) increased proliferation and decreased apoptosis after TMZ treatment. Antioxidative effects of TMZ were observed in both VSMCs and HUVECs. ConclusionsReduction of restenosis by TMZ treatment involved changes in antioxidative and anti-inflammatory properties, which are cell-specific effects on either survival or apoptosis. The specific actions and physiological effects of TMZ may contribute to better understanding of the pathogenesis of atherosclerosis, which is a major complication of diabetes mellitus.

Wpływ stentowania tętnicy udowej powierzchownej i poszczególnych czynników ryzyka wystąpienia miażdżycy na zmiany wybranych parametrów globalnej funkcji śródbłonka u pacjentów z przewlekłym niedokrwieniem kończyn dolnych. Badanie pilotażowe

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Budzyński J, Wiśniewska J, Wasielewski M, Suppan K. Original paperThe effect of superficial femoral artery stenting and some atherosclerosis risk factors on changes in selected global endothelial function tests in patients with chronic lower limb ischemia. A pilot study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. 2012;8(3):205-215. doi:10.5114/pwki.2012.30400. APA Budzyński, J., Wiśniewska, J., Wasielewski, M., & Suppan, K. (2012). Original paperThe effect of superficial femoral artery stenting and some atherosclerosis risk factors on changes in selected global endothelial function tests in patients with chronic lower limb ischemia. A pilot study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej, 8(3), 205-215. https://doi.org/10.5114/pwki.2012.30400 Chicago Budzyński, Jacek, Joanna Wiśniewska, Marcin Wasielewski, and Karol Suppan. 2012. "Original paperThe effect of superficial femoral artery stenting and some atherosclerosis risk factors on changes in selected global endothelial function tests in patients with chronic lower limb ischemia. A pilot study". Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej 8 (3): 205-215. doi:10.5114/pwki.2012.30400. Harvard Budzyński, J., Wiśniewska, J., Wasielewski, M., and Suppan, K. (2012). Original paperThe effect of superficial femoral artery stenting and some atherosclerosis risk factors on changes in selected global endothelial function tests in patients with chronic lower limb ischemia. A pilot study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej, 8(3), pp.205-215. https://doi.org/10.5114/pwki.2012.30400 MLA Budzyński, Jacek et al. "Original paperThe effect of superficial femoral artery stenting and some atherosclerosis risk factors on changes in selected global endothelial function tests in patients with chronic lower limb ischemia. A pilot study." Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej, vol. 8, no. 3, 2012, pp. 205-215. doi:10.5114/pwki.2012.30400. Vancouver Budzyński J, Wiśniewska J, Wasielewski M, Suppan K. Original paperThe effect of superficial femoral artery stenting and some atherosclerosis risk factors on changes in selected global endothelial function tests in patients with chronic lower limb ischemia. A pilot study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. 2012;8(3):205-215. doi:10.5114/pwki.2012.30400.

Soluble Guanylate Cyclase α1β1 Limits Stroke Size and Attenuates Neurological Injury

Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the alpha(1) subunit of sGC (sGCalpha(1)(-/-)) with that in wild-type mice. Blood pressure, cerebrovascular anatomy, and vasoreactivity of pressurized carotid arteries were compared in both mouse genotypes. Cerebral blood flow was measured before and during middle cerebral artery occlusion and reperfusion. We then assessed neurological deficit and infarct volume after 1 hour of occlusion and 23 hours of reperfusion and after 24 hours of occlusion. Blood pressure and cerebrovascular anatomy were similar between genotypes. We found that vasodilation of carotid arteries in response to acetylcholine or sodium nitroprusside was diminished in sGCalpha(1)(-/-) compared with wild-type mice. Cerebral blood flow deficits did not differ between the genotypes during occlusion, but during reperfusion, cerebral blood flow was 45% less in sGCalpha(1)(-/-) mice. Infarct volumes and neurological deficits were similar after 24 hours of occlusion in both genotypes. After 1 hour of ischemia and 23 hours of reperfusion, infarct volumes were 2-fold larger and neurological deficits were worse in sGCalpha(1)(-/-) than in the wild-type mice. sGCalpha(1) deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, suggesting that cGMP generated by sGCalpha(1)beta(1) is protective in ischemic stroke.

Vascular smooth cell proliferation in perfusion culture of porcine carotid arteries

Objective of this study was to develop a novel in vitro artery culture system to study vascular smooth muscle cell (SMC) proliferation of porcine carotid arteries in response to injury, basic fibroblast growth factor (FGF2), and FGF2 conjugated with cytotoxin saporin (SAP). Perfusion-cultured porcine carotid arteries remained contractile in response to norepinephrine and relaxant to acetylcholine for up to 96 h. SMC proliferation of cultured arteries was detected by bromodeoxyuridine incorporation in both non-injured and balloon-injured arteries. In the inner layer of the vessel wall near the lumen, SMC proliferation were less than 10% in uninjured vessels, 66% in injured vessels, 80% in injured vessels with FGF2 treatment, and 5% in injured vessels with treatment of FGF2-SAP. Thus, the cultured porcine carotid arteries were viable; and the injury stimulated SMC proliferation, which was significantly enhanced by FGF2 and inhibited by FGF2-SAP.

Peripheral changes above and below injury level lead to prolonged vascular responses following high spinal cord injury

Autonomic dysreflexia (AD) is a debilitating disorder producing episodes of extreme hypertension in patients with high-level spinal cord injury (SCI). Factors leading to AD include loss of vasomotor baroreflex control to regions below injury level, changes in spinal circuitry, and peripheral changes. The present study tested for peripheral changes below and above injury level 6 wk after a transection at the fourth thoracic spinal level. Changes in vascular conductance were recorded in the femoral, renal, brachial, and carotid arteries in response to intravenous injections of two alpha-adrenergic agonists, phenylephrine (PE; 0.03-100 microg/kg) and methoxamine (Meth; 1-300 microg/kg). Unlike PE, Meth is not subject to neuronal reuptake. Ganglionic blockade (0.6 mg/kg chlorisondamine) was used to eliminate the central component of the cardiovascular response. After ganglionic blockade, SCI animals exhibited prolonged vasoconstriction in response to PE in all blood vessels measured compared with those in intact animals (all, P < 0.035). However, the PE dose-response curves obtained after ganglionic blockade revealed no significant difference in the potency between the two groups (all, P > 0.06), indicating that the prolonged vasoconstriction was not due to supersensitivity to PE. In contrast to PE, vascular responses to Meth did not vary between intact and SCI groups (all P > 0.108). These results show the development of a widespread peripheral change producing prolonged vasoconstriction in response to PE, but not Meth, possibly due to reduced neuronal reuptake of PE after SCI. This is the first study to report such a change in blood vessels not only below but also above injury level. Interventions to correct this reduced reuptake may help limit the development of AD.

Rat Carotid Artery Responses to α‐Adrenergic Receptor Agonists and 5‐HT After Ovariectomy and Hormone Replacement

To compare the contractile responses to alpha-adrenergic receptor agonists and 5-HT in the rat carotid artery after ovariectomy and subsequent hormone replacement with 17beta-estradiol, progesterone, or the combination of 17beta-estradiol and progesterone. The prevalence of migraine is higher in women than in men, and changes in 17beta-estradiol levels seem to affect the frequency of attacks in female migraineurs. However, the underlying mechanisms are not yet completely understood. After 1 week of acclimatization (Day 0), female Sprague-Dawley rats were either sham-operated or bilateral ovariectomized. One week later (Day 7), the ovariectomized rats were subcutaneously implanted with a pellet releasing over a 21-day period either placebo, 0.25 mg 17beta-estradiol, 50 mg progesterone, or the combination of the 2 hormones. Blood samples were collected on Days 0, 7, and 21 to measure plasma norepinephrine and epinephrine. On days 25 to 28, the animals were killed to isolate carotid artery and mount its segments in Mulvany myographs. Cumulative concentration response curves to alpha-adrenergic receptor agonists and 5-HT were constructed in the absence or presence of suitable antagonists. The potency of norepinephrine in ovariectomized rats was significantly reduced in animals treated with progesterone as compared to those with placebo. In placebo-treated ovariectomized animals there was a noticeable response mediated by alpha2-adrenoceptors, in contrast to that in sham-operated or ovariectomized rats treated with 17beta-estradiol and progesterone, either alone or in combination. The plasma levels of norepinephrine and epinephrine were not significantly affected by either ovariectomy or the subsequent hormone replacement. The potency of 5-HT was significantly reduced in animals having circulating sex hormones as compared to that in placebo-treated ovariectomized animals. Taken together, our results indicate that circulating progesterone and/or 17beta-estradiol may reduce the contraction of the rat carotid artery in response to norepinephrine and 5-HT. This effect of female sex hormones might be one of the factors through which these hormones aggravate migraine in women.

Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats

When increased in vascular tissues, angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase that hydrolyzes angiotensin II to angiotensin-(1-7), may augment the growth inhibitory and vasodilatory effects of the heptapeptide. We investigated the regulation of ACE2 and angiotensin-(1-7) expression in aortas and carotid arteries of 12-wk-old male spontaneously hypertensive rats (SHR) by determining the effect of sustained angiotensin type 1 (AT(1)) receptor blockade with olmesartan (10 mg.kg(-1).day(-1), n = 13) compared with those that received atenolol (30 mg.kg(-1).day(-1), n = 13), hydralazine (10 mg.kg(-1).day(-1), n = 13), or vehicle (n = 21). Systolic blood pressures were approximately 30% lower (P < 0.05) in rats treated for 2 wk with olmesartan compared with vehicle-treated rats. Both atenolol and hydralazine produced similar decreases in systolic blood pressure. ACE2 mRNA in the thoracic aorta of olmesartan-treated rats (n = 8) was fivefold greater (P < 0.05) than that in vehicle-treated rats (n = 16), whereas atenolol (n = 8) or hydralazine (n = 8) had no effect. Immunostaining intensities in rats treated with olmesartan (n = 5) were also associated with increased (P < 0.05) ACE2 and angiotensin-(1-7) in thoracic aorta media compared with vehicle-treated rats. In contrast, immunostaining intensities for both ACE2 and angiotensin-(1-7) were not different from vehicle (n = 5) in carotid arteries of SHR medicated with either atenolol (n = 5) or hydralazine (n = 5). A comparison of vessel wall dimensions showed that olmesartan selectively reduced the thoracic aorta media-to-lumen ratio (P < 0.05) and media thickness (P < 0.05) without an effect on carotid artery morphometry. Compared with vehicle-treated SHR, vascular hypertrophy determined from media and lumen measurements was not changed in SHR given either atenolol or hydralazine. These data represent the first report of ACE2 and angiotensin-(1-7) expression in the aorta and carotid arteries of SHR. Increased ACE2 and angiotensin-(1-7) in association with altered dimensions of the thoracic aorta but not carotid arteries in response to olmesartan treatment provides evidence that this pathway is regulated by AT(1) receptors and may be important in mediating the pressure-independent vascular remodeling effects of angiotensin peptides.

Effects of a sustained extension on arterial growth and remodeling: a theoretical study

Three recent studies reveal that the unloaded length of a carotid artery increases significantly and rapidly in response to sustained increases in axial extension. Moreover, such lengthening involves an “unprecedented” increase in the rate of turnover of cells and matrix. Although current data are not sufficient for detailed biomechanical analyses, we present general numerical simulations that are consistent with the reported observations and support the hypothesis that rates of turnover correlate with the extent that stresses are perturbed from normal. In particular, a 3-D analysis of wall stress suggests that moderate (15%) increases in axial extension can increase the axial stress to a much greater extent than marked (50%) increases in blood pressure increase the circumferential stress. Furthermore, such increases in axial stress can occur without inducing significant gradients in stress within the wall. Consequently, we use a new, 2-D constrained mixture model to study evolving changes in the geometry, structure, and properties of carotid arteries in response to a sustained increase in axial extension. These simulations are qualitatively similar to the reports in the literature and support the notion that the stress-free lengths of individual constituents evolve during growth and remodeling.

Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice.

Increased superoxide is thought to play a major role in vascular dysfunction in a variety of disease states. Superoxide dismutase (SOD) limits increases in superoxide; however, the functional significance of selected isoforms of SOD within the vessel wall are unknown. We tested the hypothesis that selective loss of CuZnSOD results in increased superoxide and altered vascular responsiveness in CuZnSOD-deficient (CuZnSOD(-/-)) mice compared with wild-type (CuZnSOD(+/+)) littermates. Total SOD activity was reduced (P<0.05) by approximately 60% and CuZnSOD protein was absent in aorta from CuZnSOD(-/-) as compared with wild-type mice. Vascular superoxide levels, measured using lucigenin (5 micro mol/L)-enhanced chemiluminescence and hydroethidine (2 micro mol/L)-based confocal microscopy, were increased (approximately 2-fold; P<0.05) in CuZnSOD(-/-) mice as compared with wild-type mice. Relaxation of the carotid artery in response to acetylcholine and authentic nitric oxide was impaired (P<0.05) in CuZnSOD(-/-) mice. For example, maximal relaxation to acetylcholine (100 micro mol/L) was 50+/-6% and 69+/-5% in CuZnSOD(-/-) and wild-type mice, respectively. Contractile responses of the carotid artery were enhanced (P<0.05) in CuZnSOD(-/-) mice in response to phenylephrine and serotonin, but not to potassium chloride or U46619. In vivo, dilatation of cerebral arterioles (baseline diameter=31+/-1 micro m) to acetylcholine was reduced by approximately 50% in CuZnSOD(-/-) mice as compared with wild-type mice (P<0.05). These findings provide the first direct insight into the functional importance of CuZnSOD in blood vessels and indicate that this specific isoform of SOD limits increases in superoxide under basal conditions. CuZnSOD-deficiency results in altered responsiveness in both large arteries and microvessels.