Increased Endothelial Exocytosis and Generation of Endothelin-1 Contributes to Constriction of Aged Arteries

Goel, Aditya; Su, Baogen Y.; Flavahan, Sheila; Lowenstein, Charles J.; Berkowitz, Dan E.; Flavahan, Nicholas A.

doi:10.1161/circresaha.109.210229

Cited by 59 publications

(67 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition to these issues, we also studied aged offspring rather than young offspring because enhanced ET-1 signaling has been shown to be a mechanism involved in the increased vascular tone associated with aging. 18 A marked difference was observed between aged male and female offspring in vascular conversion of bET-1 to ET-1, Table S1 in the onlineonly Data Supplement. as well as BP reliance on ET-1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Hypoxia Causes Long-Term Alterations in Vascular Endothelin-1 Function in Aged Male, but Not Female, Offspring

et al. 2013

View full text Add to dashboard Cite

Fetal hypoxia is believed to be an important pathogenetic factor in a number of pregnancy-related complications such as preeclampsia and intrauterine growth restriction (IUGR). Numerous epidemiological and animal studies have shown that stressors such as hypoxia can influence the growth and developmental trajectories of the fetus, thereby increasing its susceptibility to long-term health complications, including cardiovascular diseases (reviewed in Rueda-Clausen et al 1 ). In support of this, we and others have shown that prenatal hypoxia is associated with long-term alterations in vascular function, characterized by reduced NO-mediated vasodilation, as well as increased responsiveness to adrenergic vasoconstrictors. [2][3][4] ET-1 is a polypeptide that plays an integral role in vascular function. By virtue of its potent vasoconstrictor properties and its capacity to induce vascular remodeling, ET-1 signaling is believed to be important in the progression of diseases where vascular dysfunction plays a role. 5,6 The vasoactive peptide ET-1 is synthesized as an inactive precursor, big ET-1 (bET-1), which is then subsequently cleaved by 1 of several enzymes, including the endothelin (ET)-converting enzymes (ECE), certain members of the matrix-metalloproteinase (MMP) family (notably the gelatinases), chymase and neutral endopeptidase. 7 Recently, we showed that NO plays a role in regulating the conversion of bET-1 to active ET-1, 8 and consequently conditions of NO deficiency, such as IUGR, may also be associated with increased ET-1 activity. Collectively, these studies provided us the impetus to investigate whether prenatal hypoxia confers on the offspring an altered circulatory phenotype, characterized by increased ET-1 signaling, and determine whether male and female offspring were similarly affected. MethodsExpanded methods are available in the online-only Data Supplement. Briefly, the experimental protocols described herein were approved by the University of Alberta Health Sciences Animal Policy and Welfare Committee in accordance with the See Editorial Commentary, pp 685-686Abstract-Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1-induced vasoconstriction compared with controls (n=7 per group; P<0.001); NO synthase inhibition with L-N G -nitroarginine-methyl ester potentiated bET-1-induced vasoconstriction, albeit this effect was 2-fold greater (P<0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n=9-11 per group). In the presence of L-N G -nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymosta...

show abstract

Section: Discussionmentioning

confidence: 99%

Prenatal Hypoxia Causes Long-Term Alterations in Vascular Endothelin-1 Function in Aged Male, but Not Female, Offspring

et al. 2013

View full text Add to dashboard Cite

show abstract

“…27,28 NOS inhibitor for 35 minutes also failed to increase ET-1 release in rat aorta. 30 In bovine aorta, NOS inhibitor caused a nonstatistically significant increase in ET-1 release and, moreover, the increase was observed after 4.3-hour NOS inhibitor exposure. 29 In the one study performed in an isolated perfused preparation in which ET-1 release was measured, the rat mesenteric arterial bed, pretreatment with combined NOS inhibitor, methylene blue (inhibitor of NO activation of guanylate cyclase), tetraethylammonium (nonselective K + -channel blocker), and indomethacin (cycloxygenase inhibitor) increased ET-1 release at a flow rate of 30 mL/min but not at 5 mL/min, as assayed in perfusate recirculated through the vascular bed for 2 hours 31 ( Figure).…”

mentioning

confidence: 89%

“…Investigations of ET-1 release in isolated arteries were largely limited to static preparations (ie, nonperfused and unstretched vessels; [27][28][29][30] Figure). In porcine aorta, even prolonged exposure (4 and 9 hours) to NOS inhibitor failed to increase ET-1 release.…”

mentioning

confidence: 99%

Nitric Oxide Inhibition of Endothelin-1 Release in the Vasculature

Rapoport

2014

Hypertension

View full text Add to dashboard Cite

A key function of endothelial derived nitric oxide (NO) is to limit the constrictor capacity of endothelin (ET)-1.1,2 Thus, an imbalance between NO and ET-1 can result in ET-1-dependent increased vascular tone.1 Indeed, the importance of sustained, NO inhibition of the ET-1 drive to increase tone is exemplified in vivo by the rapid, ET-1-mediated arterial pressure elevation after acute NO synthase (NOS) inhibition. Moreover, the ET-1 pressor effect after NOS inhibition is independent of other pressor systems and, thus, reflects the relative importance of NO suppression of this ET-1 drive.2 Two, nonmutually exclusive mechanisms thought to underlie the ET-1 dependency of the increased vascular tone responsible for the NOS inhibitor-induced pressure elevation are (1) NO inhibition of constriction to endogenously released ET-1.1,2 This mechanism is essentially supported by demonstrations that NOS inhibitor enhanced the constrictor effects of exogenous ET-1 in several in vivo and ex vivo preparations. 3-14Thus, an assumption underlying these observations is that the constrictor actions of exogenous and endogenous ET-1 are similarly affected by NO; (2) NO inhibition of ET-1 release. 1,2Although the detailed mechanism underlying the NO inhibition of acute ET-1 release has not been clearly established, possibilities include decreased conversion of the immediate precursor to ET-1, big ET-1, to ET-1 15 and inhibition of pathways involved in the exocytosis of Weibel-Palade bodies, 16 endothelial granules that store ET-1. 17 However, it should be noted that in vivo findings that actually demonstrate the fundamental phenomenon of NO inhibition of ET-1 release are generally lacking.2 Thus, studies purported to demonstrate NO inhibition of ET-1 release have relied largely on isolated vessels and cultured endothelium, as described herein.This review assessed these in vitro findings, with a specific focus toward elucidating the mechanism underlying the NO-mediated negative regulation of ET-1-dependent increased arterial pressure, as demonstrated after acute NOS inhibitor in vivo.2 Findings referred to are mainly those of ET-1 release rather than contractility (eg, those in which ET receptor antagonist prevented the NOS inhibitor-induced decreased flow/increased pressure/tension). 12,18-25 The rationale for this emphasis is that findings based on contractility could reflect NOS inhibitor enhancement of ET-1 constriction rather than increased ET-1 release. Furthermore, we also focus on whether laminar shear stress influences the manifestation of NO inhibition of ET-1 release. That is, the endothelium of arteries that are anatomically linear is subjected to high levels of shear stress while, for example, at bifurcated arterial locations is subjected to low levels of shear stress, regions associated with atherosclerosis. 26 Acute NOS Inhibition/No Donors and ET-1 Release ArteriesIn rat heart perfused at constant flow, increased amounts of ET-1 were detected in the coronary effluent of samples collected for the final 5 to 15 minutes ...

show abstract

“…13,14 Likewise, the evidence linking acute release of endothelin-1 to constriction of arteries is still limited. 15 Therefore, the present article focuses on the mechanisms leading to the production of endothelial COX-derived vasoconstrictors, in particular, in the rat aorta, which has been the standard preparation used by the author and his collaborators for the study of EDCF-mediated responses However, the occurrence of such EDCF-mediated responses can vary widely, depending on the species and the blood vessel studied. For example, they are prominent in canine veins but not arteries.…”

mentioning

confidence: 99%

Endothelium-Dependent Contractions in Hypertension

2011

View full text Add to dashboard Cite

M ost isolated arteries respond to shear stress and several vasodilator substances, as demonstrated first for acetylcholine, 1 by releasing endothelium-derived relaxing factor (or nitric oxide [NO]), and various endothelium-derived hyperpolarizing signals. [2][3][4][5] However, in certain blood vessels, when exposed to stretch, agonists such as thrombin, acetylcholine, and adenosine nucleotides (adenosine diphosphate [ADP] and adenosine triphosphate [ATP]) or calcium ionophores, the endothelium produces diffusible cyclooxygenase (COX)-derived vasoconstrictor prostanoids (endotheliumderived contracting factors [EDCF]) 6 -11 Endothelial cells also produce vasoconstrictor peptides, in particular, endothelin-1. 12 The attribution of a role to endothelin-1 in instantaneous changes in vascular tone has been made difficult by the almost insurmountable nature of the vasoconstriction caused by the peptide that can only be tempered by NO or calcitonin gene-related peptide. 13,14 Likewise, the evidence linking acute release of endothelin-1 to constriction of arteries is still limited. 15 Therefore, the present article focuses on the mechanisms leading to the production of endothelial COX-derived vasoconstrictors, in particular, in the rat aorta, which has been the standard preparation used by the author and his collaborators for the study of EDCF-mediated responses However, the occurrence of such EDCF-mediated responses can vary widely, depending on the species and the blood vessel studied. For example, they are prominent in canine veins but not arteries. 6 In the mouse, endothelium-dependent contractions are more pronounced in the carotid artery than in the aorta. 16,17 Further, in any given blood vessel, the production of endothelium-derived vasoconstrictor prostanoids is exacerbated by aging and disease, in particular, hypertension. 10,11,18,19 The Trigger: Calcium Acetylcholine (which activates endothelial M3-muscarinic receptors) 20 and ADP and ATP (which activate endothelial purinoceptors) 21,22 evoke endothelium-dependent contractions and release of calcium from the sarcoplasmic reticulum. 23 Lowering the extracellular calcium concentration reduces endothelium-dependent contractions, 24 whereas calcium ionophores, in particular, A23187, evoke endotheliumdependent contractions. [25][26][27][28][29] During endothelium-dependent contractions induced by acetylcholine, the endothelial cytosolic calcim concentration increases 28,29 and this increment is larger in aortae of spontaneously hypertensive rats (SHR) than in those of normotensive Wistar-Kyoto rats, in line with the larger EDCF-mediated responses in the preparations of the hypertensive strain. 8,28,30 Taken in conjunction, those findings imply that an increase in endothelial cytosolic calcium concentration is the initiating event leading to the release of EDCF. In the case of acetylcholine, the muscarinic agonist binds to G-protein-coupled M 3 receptors on the endothelial cell membrane and activates phospholipase C, which produces inositol triphosphate, causing...

show abstract

Increased Endothelial Exocytosis and Generation of Endothelin-1 Contributes to Constriction of Aged Arteries

Cited by 59 publications

References 54 publications

Prenatal Hypoxia Causes Long-Term Alterations in Vascular Endothelin-1 Function in Aged Male, but Not Female, Offspring

Prenatal Hypoxia Causes Long-Term Alterations in Vascular Endothelin-1 Function in Aged Male, but Not Female, Offspring

Nitric Oxide Inhibition of Endothelin-1 Release in the Vasculature

Endothelium-Dependent Contractions in Hypertension

Contact Info

Product

Resources

About