scholarly journals Can Myogenic Tone Protect Endothelial Function? Integrating Myogenic Activation and Dilator Reactivity for Cerebral Resistance Arteries in Metabolic Disease

2021 ◽  
pp. 1-15
Author(s):  
Brayden D. Halvorson ◽  
John J. McGuire ◽  
Krishna K. Singh ◽  
Joshua T. Butcher ◽  
Julian H. Lombard ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Group Treatment ◽  
Vascular Function ◽  
Cerebral Arteries ◽  
Resistance Arteries ◽  
Multiple Risk Factors ◽  
Cerebrovascular Function ◽  
Obese Zucker Rat ◽  
Middle Cerebral Arteries ◽  
Slope Treatment

The obese Zucker rat (OZR) manifests multiple risk factors for impaired cerebrovascular function, including hypertension and insulin resistance although how they combine to produce integrated vascular function is unclear. As studies have suggested that myogenic activation (MA) severity for middle cerebral arteries (MCAs) may be proportional to hypertension severity, we hypothesized that MA will negatively correlate with dilator reactivity in OZR. MA of MCA from OZR was divided into low, medium, and high based on the slope of MA, while MCA reactivity and vascular metabolite bioavailability were assessed in all groups. Endothelium-dependent dilation of MCA in OZR was attenuated and correlated with the MA slope. Treatment of OZR MCA with TEMPOL (antioxidant) improved dilation in low or medium MA groups, but had less impact on high MA. Alternatively, treatment with gadolinium to normalize MA in OZR had reduced impact on dilator reactivity in MCA from low and medium MA groups, but improved responses in the high group. Treatment with both agents resulted in dilator responses that were comparable across all groups. These results suggest that, under conditions with stronger MA, endothelial function may receive some protection despite the environment, potentially from the ability of MCA to reduce wall tension despite increased pressure.

scholarly journals Restoration of Endothelial Function inPparα−/−Mice by Tempol

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Neerupma Silswal ◽  
Nikhil Parelkar ◽  
Jon Andresen ◽  
Michael J. Wacker
Keyword(s):  
Endothelial Function ◽  
Cerebral Arteries ◽  
Lipoprotein Metabolism ◽  
Vascular Wall ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Resistance Arteries ◽  
Peroxisome Proliferator Activated Receptor ◽  
Middle Cerebral Arteries ◽  
Ros Scavenger

Peroxisome proliferator activated receptor alpha (PPARα) is one of the PPAR isoforms belonging to the nuclear hormone receptor superfamily that regulates genes involved in lipid and lipoprotein metabolism. PPARαis present in the vascular wall and is thought to be involved in protection against vascular disease. To determine if PPARαcontributes to endothelial function, conduit and cerebral resistance arteries were studied inPparα−/−mice using isometric and isobaric tension myography, respectively. Aortic contractions to PGF2αand constriction of middle cerebral arteries to phenylephrine were not different between wild type (WT) andPparα−/−; however, relaxation/dilation to acetylcholine (ACh) was impaired. There was no difference in relaxation between WT andPparα−/−aorta to treatment with a nitric oxide (NO) surrogate indicating impairment in endothelial function. Endothelial NO levels as well as NO synthase expression were reduced inPparα−/−aortas, while superoxide levels were elevated. Two-week feeding with the reactive oxygen species (ROS) scavenger, tempol, normalized ROS levels and rescued the impaired endothelium-mediated relaxation inPparα−/−mice. These results suggest thatPparα−/−mice have impaired endothelial function caused by decreased NO bioavailability. Therefore, activation of PPARαreceptors may be a therapeutic target for maintaining endothelial function and protection against cardiovascular disease.

Effect of Tetrahydrobiopterin on Endothelial Function in Canine Middle Cerebral Arteries

1996 ◽  
Vol 79 (2) ◽  
pp. 336-342 ◽  
Author(s):  
Masato Tsutsui ◽  
Sheldon Milstien ◽  
Zvonimir S. Katusic
Keyword(s):  
Endothelial Function ◽  
Cerebral Arteries ◽  
Middle Cerebral Arteries

scholarly journals Hepatic Encephalopathy-Associated Cerebral Vasculopathy in Acute-on-Chronic Liver Failure: Alterations on Endothelial Factor Release and Influence on Cerebrovascular Function

2020 ◽  
Vol 11 ◽  
Author(s):  
Laura Caracuel ◽  
Esther Sastre ◽  
María Callejo ◽  
Raquel Rodrigues-Díez ◽  
Ana B. García-Redondo ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Liver Failure ◽  
Cerebral Arteries ◽  
Chronic Liver ◽  
Chronic Liver Failure ◽  
Cerebrovascular Function ◽  
Liver Decompensation ◽  
Middle Cerebral Arteries ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F1α releases were increased, whereas thromboxane (TX) B2 was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI2 synthase, and TXA2S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE.

scholarly journals Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation

2018 ◽  
Vol 39 (8) ◽  
pp. 1570-1587 ◽  
Author(s):  
Christian Staehr ◽  
Lise Hangaard ◽  
Elena V Bouzinova ◽  
Sukhan Kim ◽  
Rajkumar Rajanathan ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Function ◽  
Cerebral Arteries ◽  
Point Mutations ◽  
Familial Hemiplegic Migraine ◽  
Laser Speckle ◽  
Hemiplegic Migraine ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca

Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point-mutations in the Na,K-ATPase α2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2+/−G301R) with wild type (WT). Middle cerebral (MCA) and mesenteric small artery (MSA) function was compared in an isometric myograph. Cerebral blood flow was assessed with Laser speckle analysis. Intracellular Ca2+ and membrane potential were measured simultaneously. Protein expression was semi-quantified by immunohistochemistry. Protein phosphorylation was analysed by Western blot. MSA from Atp1a2+/−G301R and WT showed similar contractile responses. The Atp1a2+/−G301R MCA constricted stronger to U46619, endothelin and potassium compared to WT. This was associated with an increased depolarization, although the Ca2+ change was smaller than in WT. The enhanced constriction of Atp1a2+/−G301R MCA was associated with increased cSrc activation, stronger sensitization to [Ca2+]i and increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2+/−G301R mice had reduced resting blood flow through MCA in comparison with WT mice . FHM2-associated mutation leads to elevated contractility of MCA due to sensitization of the contractile machinery to Ca2+, which is mediated via Na,K-ATPase/Src-kinase/MYPT1 signalling.

scholarly journals Angiotensin-(1-7) and low-dose angiotensin II infusion reverse salt-induced endothelial dysfunction via different mechanisms in rat middle cerebral arteries

2010 ◽  
Vol 299 (4) ◽  
pp. H1024-H1033 ◽  
Author(s):  
Matthew J. Durand ◽  
Gábor Raffai ◽  
Brian D. Weinberg ◽  
Julian H. Lombard
Keyword(s):  
Endothelial Dysfunction ◽  
Receptor Antagonist ◽  
Intravenous Infusion ◽  
Low Dose ◽  
Cerebral Arteries ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Mas Receptor ◽  
Middle Cerebral Arteries

The goals of this study were to 1) determine the acute effect of ANG-(1-7) on vascular tone in isolated middle cerebral arteries (MCAs) from Sprague-Dawley rats fed a normal salt (NS; 0.4% NaCl) diet, 2) evaluate the ability of chronic intravenous infusion of ANG-(1-7) (4 ng·kg−1·min−1) for 3 days to restore endothelium-dependent dilation to acetylcholine (ACh) in rats fed a high-salt (HS; 4% NaCl) diet, and 3) determine whether the amelioration of endothelial dysfunction by ANG-(1-7) infusion in rats fed a HS diet is different from the protective effect of low-dose ANG II infusion in salt-fed rats. MCAs from rats fed a NS diet dilated in response to exogenous ANG-(1-7) (10−10–10−5 M). Chronic ANG-(1-7) infusion significantly reduced vascular superoxide levels and restored the nitric oxide-dependent dilation to ACh (10−10–10−5 M) that was lost in MCAs of rats fed a HS diet. Acute vasodilation to ANG-(1-7) and the restoration of ACh-induced dilation by chronic ANG-(1-7) infusion in rats fed a HS diet were blocked by the Mas receptor antagonist [d-ALA( 7 )]-ANG-(1-7) or the ANG II type 2 receptor antagonist PD-123319 and unaffected by ANG II type 1 receptor blockade with losartan. The restoration of ACh-induced dilation in MCAs of HS-fed rats by chronic intravenous infusion of ANG II (5 ng·kg−1·min−1) was blocked by losartan and unaffected by d-ALA. These findings demonstrate that circulating ANG-(1-7), working via the Mas receptor, restores endothelium-dependent vasodilation in cerebral resistance arteries of animals fed a HS diet via mechanisms distinct from those activated by low-dose ANG II infusion.

scholarly journals Peroxynitrite Decomposition with FeTMPyP Improves Plasma-Induced Vascular Dysfunction and Infarction during Mild but not Severe Hyperglycemic Stroke

2012 ◽  
Vol 32 (6) ◽  
pp. 1035-1045 ◽  
Author(s):  
Sara Morales Palomares ◽  
Ira Gardner-Morse ◽  
Julie G Sweet ◽  
Marilyn J Cipolla
Keyword(s):  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Stroke Outcome ◽  
Cerebrovascular Function ◽  
Middle Cerebral Arteries ◽  
Male Wistar Rats ◽  
Physiologic Saline ◽  
Severe Ischemia

We investigated mechanisms by which circulating factors during hyperglycemic (HG) stroke affect cerebrovascular function and the role of peroxynitrite in stroke outcome. Middle cerebral arteries (MCAs) were isolated from male Wistar rats and perfused with plasma from rats that were hyperglycemic for 5 to 6 days by streptozotocin and underwent either MCA occlusion (HG MCAO) or Sham surgery (HG Sham) compared with MCA perfused with physiologic saline (No plasma). Myogenic responses and endothelial function were compared in untreated MCA ( n=8/group) or with inhibitors of NADPH oxidase (apocynin; n=8), peroxynitrite (FeTMPyP; n=8) or endothelin-1 (ET-1)A (BQ-123; n=8). Finally, animals were treated in vivo before reperfusion after mild (<68% cerebral blood flow (CBF) decrease) or severe (>68% CBF decrease) MCAO with FeTMPyP ( n=12) or vehicle ( n=12) and CBF and infarction measured. The HG MCAO plasma increased tone in MCA versus No plasma ( P<0.05) that was reversed by FeTMPyP, but not by apocynin or BQ-123. The HG Sham plasma also increased tone in MCA ( P<0.05) that was reversed by BQ-123 only. In vivo, FeTMPyP was neuroprotective during mild, but not severe ischemia. These results show that circulating factors in plasma can affect cerebrovascular function through peroxynitrite generation and ET-1. In addition, peroxynitrite decomposition improves stroke outcome acutely during mild, but not severe HG ischemia.

Impaired endothelium-mediated relaxation in isolated cerebral arteries from insulin-resistant rats

2002 ◽  
Vol 282 (6) ◽  
pp. H2060-H2065 ◽  
Author(s):  
Benedek Erdös ◽  
Allison W. Miller ◽  
David W. Busija
Keyword(s):  
Vascular Function ◽  
Cerebral Arteries ◽  
Calcium Ionophore ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Control Mechanisms ◽  
Control Groups ◽  
Insulin Resistant ◽  
Middle Cerebral Arteries ◽  
And Control

Insulin resistance (IR) impairs vascular responses in peripheral arteries. However, the effects of IR on cerebrovascular control mechanisms are completely unexplored. We examined the vascular function of isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats. Endothelium-dependent vasodilation elicited by bradykinin (BK) was reduced in IR compared with control MCAs. Maximal dilation to BK (10−6 M) was 38 ± 3% ( n = 13) in control and 19 ± 3% ( n = 10) in IR arteries ( P < 0.01). N ω-nitro-l-arginine methyl ester (l-NAME; 10 μM) decreased responses to BK in control arteries by ∼65% and inhibited the already reduced responses completely in IR MCAs. Indomethacin (10 μM) reduced relaxation to BK in control MCAs by ∼40% but was largely ineffective in IR arteries. Combined l-NAME and indomethacin treatments eliminated the BK-induced dilation in both groups. Similarly to BK, endothelium-mediated and mainly cyclooxygenase (COX)-dependent dilation to calcium ionophore A23187 was reduced in IR arteries compared with controls. In contrast, vascular relaxation to sodium nitroprusside was similar between the IR and control groups. These findings demonstrate that endothelium-dependent dilation in cerebral arteries is impaired in IR primarily because of a defect of the COX-mediated pathways. In contrast, nitric oxide-mediated dilation remains intact in IR arteries.

scholarly journals Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5BN consomic rats

2012 ◽  
Vol 124 (5) ◽  
pp. 333-342 ◽  
Author(s):  
Kathleen M. Lukaszewicz ◽  
John R. Falck ◽  
Vijaya L. Manthati ◽  
Julian H. Lombard
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Dienoic Acid ◽  
Brown Norway ◽  
No Donor ◽  
Middle Cerebral Arteries ◽  
No Bioavailability ◽  
Relaxation Responses

The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NGnitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.

Development of fetal vascular responses to endothelin-1 and acetylcholine in the sheep

2001 ◽  
Vol 280 (2) ◽  
pp. R554-R562 ◽  
Author(s):  
Cheryl C. Docherty ◽  
Judit Kalmar-Nagy ◽  
Marc Engelen ◽  
Peter W. Nathanielsz
Keyword(s):  
Cerebral Arteries ◽  
Renal Arteries ◽  
Resistance Arteries ◽  
Endothelin 1 ◽  
Vascular Bed ◽  
Developmental Age ◽  
Middle Cerebral Arteries ◽  
Blood Flow Control ◽  
Critical Developmental Period ◽  
Systemic Arteries

Responses to K+, endothelin-1 (ET-1), and acetylcholine (ACh) of isolated adrenal, femoral, middle cerebral, and renal arteries from fetal [110–145 days gestational age (dGA, term ∼148 dGA)] and 0- to 24-h newborn (NB) lambs were evaluated using the technique of wire myography. Responses at distinct developmental ages for each vascular bed were compared. In all arteries sensitivity to K+-induced vasoconstriction was similar at all fetal age points examined. In contrast, sensitivity to ET-1 increased with increasing fetal age in arteries from all vascular beds. The magnitude of the maximal vasoconstriction was positively correlated with GA for K+in adrenal, femoral, and cerebral arteries and for ET-1 in femoral, cerebral, and renal arteries. Cerebral arteries showed a greater sensitivity when compared with the other systemic arteries to K+ and ET-1 at all fetal ages and to K+ in NB. ACh evoked relaxatory responses in fetal and NB femoral and adrenal arteries. However, renal arteries relaxed comparatively less in response to ACh, and no vasodilation was noted in middle cerebral arteries at any age points examined. For femoral arteries ACh-induced vasorelaxation decreased with increasing GA but was restored in arteries from NB lambs. In summary, the responsiveness of isolated resistance arteries varies with developmental age in the fetal and perinatal sheep and these effects are both agonist and vascular bed specific. The augmented sensitivity in response to ET-1 of middle cerebral compared with other systemic arteries may reflect the importance of cerebral blood flow control during this critical developmental period.

scholarly journals Interactive effects of growth hormone and oestrogen on vascular responses in hypophysectomised female rats

2002 ◽  
pp. 267-274 ◽  
Author(s):  
H Gustafsson ◽  
AW Tordby ◽  
L Brandin ◽  
L Hedin ◽  
IH Jonsdottir
Keyword(s):  
Growth Hormone ◽  
Endothelial Function ◽  
Vascular Function ◽  
Control Level ◽  
Interactive Effects ◽  
Female Rats ◽  
Resistance Arteries ◽  
Beneficial Effects ◽  
Igf I ◽  
Design And Methods

OBJECTIVE: Growth hormone (GH) and oestrogen (E(2)) are associated with beneficial effects on the cardiovascular system and it is therefore of great interest to study their interactive effects on haemodynamics and vascular function. DESIGN AND METHODS: Female hypophysectomised (Hx) rats were treated for seven days with GH, E(2) or a combination of the hormones. Systolic blood pressure (SBP), heart rate (HR) and plasma insulin-like growth factor-I (IGF-I) were measured. Contractile properties and endothelial function were studied in isolated resistance arteries using the wire-myograph technique. RESULTS: Hypophysectomy, per se, caused a fall in SBP and HR, while vascular adrenergic reactivity (sensitivity to applied noradrenaline) was enhanced. Impaired acetylcholine-induced relaxation and basal release of nitric oxide, suggests endothelial dysfunction after Hx. After supplementation with GH, SBP remained low while HR increased towards the control level. GH increased plasma IGF-I, but had no effect on vascular contractility or endothelial responses. E(2) replacement resulted in blunted plasma IGF-I, while the vascular adrenergic and serotonergic responses were reinforced. Endothelial function was not improved after E(2) treatment. When GH and E(2) were given in combination, the GH-induced increase in body weight, plasma IGF-I levels and HR were counteracted by E(2). Moreover, the anticipated reinforcement of the vascular serotonergic response by E(2) was reduced. Neither E(2) nor GH+E(2) affected SBP. CONCLUSIONS: The results suggest that GH and E(2) might have interactive effects on haemodynamic and metabolic parameters, but not on the contractility or endothelial function of resistance arteries, in Hx female rats.

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