Non-endothelial cell endothelin-B receptors limit neointima formation following vascular injury

Kirkby, Nicholas S.; Duthie, Karolina; Miller, Eileen; Kotelevtsev, Yuri; Bagnall, Alan; Webb, David J.; Hadoke, Patrick W. F.

doi:10.1093/cvr/cvs137

Cited by 10 publications

(29 citation statements)

References 33 publications

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“…Mice were injected intraperitoneally with saline or increasing concentrations of PAG from E8.5, and blood pressure was measured by tail-cuff plethysmography. 29 In addition, arterial blood pressure was also measured in pregnant mice at E17.5 as described previously 30 for GYY4137 studies. In brief, mice were anesthetized by using a ketamine/ xylazine cocktail, and the carotid artery was isolated and cannulated with a Millar 1-French Mikro-Tip pressure catheter connected to a pressure transducer (ADInstruments Ltd, Oxford, UK).…”

Section: Animal Experimental Protocolmentioning

confidence: 99%

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

et al. 2013

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H ydrogen sulfide (H 2 S), a gaseous signaling molecule, promotes vasodilatation 1 and stimulates angiogenesis in the vasculature.2 H 2 S has anti-inflammatory properties 3 and is also cytoprotective against cellular damage induced by lethal hypoxia or reperfusion injury. 4,5 Cystathionine γ-lyase (CSE) is the principal enzyme responsible for the endogenous production of H 2 S.6 Chronic administration of the CSE inhibitor DL-propargylglycine (PAG) leads to elevated blood pressure and vascular remodeling in the rat, 7 and both CSE and H 2 S levels are reduced in pulmonary hypertensive rats. 8Mice genetically deficient in CSE develop age-dependent hypertension, severe hyperhomocysteinemia, and endothelial dysfunction. 9 Clearly, H 2 S has multiple roles in health and disease, 10,11 but its role in pregnancy-induced hypertension is unknown. Editorial see p 2472 Clinical Perspective on p 2522Preeclampsia is a hypertensive syndrome that affects 4% to 7% of all pregnancies and is a major contributor to maternal and fetal morbidity and mortality worldwide. 12 The exact etiology of preeclampsia is unknown; abnormal placentation 13,14 and imbalance in angiogenic factors 15,16 have been implicated in preeclampsia pathogenesis. Importantly, circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1), the endogenous inhibitor of vascular endothelial growth factor and placental Background-The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H 2 S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Methods and Results-Plasma levels of H 2 S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8-12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H 2 S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect ...

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Section: Animal Experimental Protocolmentioning

confidence: 99%

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

et al. 2013

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“…Kirkby et al [26] demonstrated that nonendothelial cell ET B receptors could limit the development of neointimal formation after wire injury using endothelial cell-specific ET B knockout mice. That is, selective deletion of ET B receptors from the endothelium had no effect on neointimal formation after vascular injury whereas a selective ET B receptor antagonist aggravated neointimal formation after vascular injury in mice [26]. Furthermore, they showed that a selective ET B receptor antagonist reversed the vasoprotective effects of a selective ET A receptor antagonist in the same model [26].…”

Section: Pathophysiological Roles Of the Etb Receptor In Vascular mentioning

confidence: 99%

“…That is, selective deletion of ET B receptors from the endothelium had no effect on neointimal formation after vascular injury whereas a selective ET B receptor antagonist aggravated neointimal formation after vascular injury in mice [26]. Furthermore, they showed that a selective ET B receptor antagonist reversed the vasoprotective effects of a selective ET A receptor antagonist in the same model [26]. These findings indicate that nonendothelial ET B receptors have aggressive vasoprotective effects and that selective ET A receptor antagonists are preferable to ET A /ET B receptor antagonists for the treatment of vascular injury.…”

Section: Pathophysiological Roles Of the Etb Receptor In Vascular mentioning

confidence: 99%

“…However, the roles of the ET B receptor on vascular injury are still controversial. Recently, it was reported that nonendothelial ET B -receptor induced vasoprotective effects, whereas another previous study demonstrated that ET B -receptor-mediated ET-1 action exhibited vasoprotective effects via NO production [25, 26]. (b) Inhibition of the ET B receptor system leads to an aggravation of vascular injury.…”

Section: Figurementioning

confidence: 99%

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Pathological Importance of the Endothelin-1/ET_BReceptor System on Vascular Diseases

Kitada

Ohkita

Matsumura

2012

Cardiology Research and Practice

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Activation of the endothelin (ET)-1/ET receptor system is involved in the development of vascular diseases such as atherosclerosis, vascular hypertrophy, and restenosis. Some issues still remain unresolved including whether ET receptor antagonists are expected to become the new therapeutic tools for the treatment of vascular diseases. One of the unresolved critical points is the functional role of ET receptor subtypes on each vascular disease, in particular the pathophysiological roles of the ETB receptor. We recently demonstrated that selective inhibition of the ETB receptor system showed harmful effects in the development of neointimal formation after vascular injury. However, there was no apparent difference in the therapeutic effects between a nonselective ETA/ETB receptor antagonist and selective ETA receptor antagonist. These findings indicate that antagonism of the ETA receptor system is essential for suppressing vascular remodeling, irrespective of the presence of ETB-receptor-mediated actions, although the selective ETB receptor antagonist worsens vascular remodeling. In addition, we found that ET receptor systems contribute to sex differences in the severity of vascular disease, thereby suggesting that the efficacy of ET receptor antagonists for vascular diseases may differ between sexes. In this paper, we outline the roles of the ET-1/ETB receptor system on vascular diseases and its sex differences.

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“…Indeed we have now used OPT to demonstrate the effect of pharmacological interventions and genetic manipulation on atherosclerotic and neointimal lesion size. For example, endothelin receptor blockade altered neointimal lesion formation whereas selective deletion of the endothelin B receptor from the vascular endothelium did not 15 . In atherosclerosis prone mice, genetic deletion of the enzymes 11β-HSD1 16 or galectin 3 17 were shown to reduce the size of atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 99%

Generation and 3-Dimensional Quantitation of Arterial Lesions in Mice Using Optical Projection Tomography

Kirkby

Low

et al. 2015

JoVE

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The generation and analysis of vascular lesions in appropriate animal models is a cornerstone of research into cardiovascular disease, generating important information on the pathogenesis of lesion formation and the action of novel therapies. Use of atherosclerosis-prone mice, surgical methods of lesion induction, and dietary modification has dramatically improved understanding of the mechanisms that contribute to disease development and the potential of new treatments.Classically, analysis of lesions is performed ex vivo using 2-dimensional histological techniques. This article describes application of optical projection tomography (OPT) to 3-dimensional quantitation of arterial lesions. As this technique is non-destructive, it can be used as an adjunct to standard histological and immunohistochemical analyses.Neointimal lesions were induced by wire-insertion or ligation of the mouse femoral artery whilst atherosclerotic lesions were generated by administration of an atherogenic diet to apoE-deficient mice.Lesions were examined using OPT imaging of autofluorescent emission followed by complementary histological and immunohistochemical analysis. OPT clearly distinguished lesions from the underlying vascular wall. Lesion size was calculated in 2-dimensional sections using planimetry, enabling calculation of lesion volume and maximal cross-sectional area. Data generated using OPT were consistent with measurements obtained using histology, confirming the accuracy of the technique and its potential as a complement (rather than alternative) to traditional methods of analysis.This work demonstrates the potential of OPT for imaging atherosclerotic and neointimal lesions. It provides a rapid, much needed ex vivo technique for the routine 3-dimensional quantification of vascular remodelling.

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Non-endothelial cell endothelin-B receptors limit neointima formation following vascular injury

Cited by 10 publications

References 33 publications

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

Pathological Importance of the Endothelin-1/ET_BReceptor System on Vascular Diseases

Generation and 3-Dimensional Quantitation of Arterial Lesions in Mice Using Optical Projection Tomography

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Non-endothelial cell endothelin-B receptors limit neointima formation following vascular injury

Cited by 10 publications

References 33 publications

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

Pathological Importance of the Endothelin-1/ETBReceptor System on Vascular Diseases

Generation and 3-Dimensional Quantitation of Arterial Lesions in Mice Using Optical Projection Tomography

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Pathological Importance of the Endothelin-1/ET_BReceptor System on Vascular Diseases