scholarly journals Contribution of epoxyeicosatrienoic acids to flow-induced dilation in arteries of male ERα knockout mice: role of aromatase

2007 ◽  
Vol 293 (3) ◽  
pp. R1239-R1246 ◽  
Author(s):  
Dong Sun ◽  
Changdong Yan ◽  
Azita Jacobson ◽  
Houli Jiang ◽  
Mairead A. Carroll ◽  
...  
Keyword(s):  
Gas Chromatography Mass Spectrometry ◽  
Epoxyeicosatrienoic Acids ◽  
Epoxyeicosatrienoic Acid ◽  
Wild Type ◽  
Electrophysiological Technique ◽  
Isolated Arteries ◽  
Oxide Synthase ◽  
Interfering Rna ◽  
Endothelial Nitric Oxide

We studied the roles of estrogen receptors (ER) and aromatase in the mediation of flow-induced dilation (FID) in isolated arteries of male ERα-knockout (ERα-KO) and wild-type (WT) mice. FID was comparable between gracilis arteries of WT and ERα-KO mice. In WT arteries, inhibition of NO and prostaglandins eliminated FID. In ERα-KO arteries, Nω-nitro-l-arginine methyl ester (l-NAME) inhibited FID by ∼26%, whereas indomethacin inhibited dilations by ∼50%. The remaining portion of the dilation was abolished by additional administration of 6-(2-proparglyoxyphenyl)hexanoic acid (PPOH) or iberiotoxin, inhibitors of epoxyeicosatrienoic acid (EET) synthesis and large-conductance potassium channels, respectively. By using an electrophysiological technique, we found that, in the presence of 10 dyne/cm2 shear stress, perfusate passing through donor vessels isolated from gracilis muscle of ERα-KO mice subjected to l-NAME and indomethacin elicited smooth muscle hyperpolarization and a dilator response of endothelium-denuded detector vessels. These responses were prevented by the presence of iberiotoxin in detector or PPOH in donor vessels. Gas chromatography-mass spectrometry (GC-MS) analysis indicated a significant increase in arterial production of EETs in ERα-KO compared with WT mice. Western blot analysis showed a significantly reduced endothelial nitric oxide synthase expression but enhanced expressions of aromatase and ERβ in ERα-KO arteries. Treatment of ERα-KO arteries with specific aromatase short-interfering RNA for 72 h, knocked down the aromatase mRNA and protein associated with elimination of EET-mediation of FID. Thus, FID in male ERα-KO arteries is maintained via an endothelium-derived hyperpolarizing factor/EET-mediated mechanism compensating for reduced NO mediation due, at least in part, to estrogen aromatized from testosterone.

scholarly journals Female-favorable attenuation of coronary myogenic constriction via reciprocal activations of epoxyeicosatrienoic acids and nitric oxide

2016 ◽  
Vol 310 (11) ◽  
pp. H1448-H1454 ◽  
Author(s):  
Ghezal Froogh ◽  
Jun Qin ◽  
Sharath Kandhi ◽  
Yicong Le ◽  
Houli Jiang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Coronary Arteries ◽  
Intraluminal Pressure ◽  
Epoxyeicosatrienoic Acids ◽  
Myogenic Response ◽  
Upward Shift ◽  
Genetic Deletion ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via CYP/epoxygenases, which are catabolized by soluble epoxide hydrolase (sEH) and known to possess cardioprotective properties. To date, the role of sEH in the modulation of pressure-induced myogenic response/constriction in coronary arteries, an important regulatory mechanism in the coronary circulation, and the issue as to whether the disruption of the sEH gene affects the myogenic response sex differentially have never been addressed. To this end, experiments were conducted on male (M) and female (F) wild-type (WT) and sEH-knockout (KO) mice. Pressure-diameter relationships were assessed in isolated and cannulated coronary arteries. All vessels constricted in response to increases in intraluminal pressure from 60 to 120 mmHg. Myogenic vasoconstriction was significantly attenuated, expressed as an upward shift in the pressure-diameter curve of vessels, associated with higher cardiac EETs in M-KO, F-WT, and F-KO mice compared with M-WT controls. Blockade of EETs via exposure of vessels to 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) prevented the attenuated myogenic constriction in sEH-KO mice. In the presence of 14,15-EEZE, pressure-diameter curves of females presented an upward shift from those of males, exhibiting a sex-different phenotype. Additional administration of Nω-nitro-l-arginine methyl ester eliminated the sex difference in myogenic responses, leading to four overlapped pressure-diameter curves. Cardiac sEH was downregulated in F-WT compared with M-WT mice, whereas expression of endothelial nitric oxide synthase and CYP4A (20-HETE synthase) was comparable among all groups. In summary, in combination with NO, the increased EET bioavailability as a function of genetic deletion and/or downregulation of sEH accounts for the female-favorable attenuation of pressure-induced vasoconstriction.

scholarly journals Role of CYP epoxygenases in A2AAR-mediated relaxation using A2AAR-null and wild-type mice

2008 ◽  
Vol 295 (5) ◽  
pp. H2068-H2078 ◽  
Author(s):  
Mohammed A. Nayeem ◽  
Samuel M. Poloyac ◽  
John R. Falck ◽  
Darryl C. Zeldin ◽  
Catherine Ledent ◽  
...  
Keyword(s):  
Epoxyeicosatrienoic Acid ◽  
Wild Type ◽  
Nitric Oxide Synthase Inhibitor ◽  
Cgs 21680 ◽  
Sch 58261 ◽  
Specific Antagonist ◽  
Synthase Inhibitor ◽  
Mouse Aorta ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We hypothesized that A2A adenosine receptor (A2AAR) activation causes vasorelaxation through cytochrome P-450 (CYP) epoxygenases and endothelium-derived hyperpolarizing factors, whereas lack of A2AAR activation promotes vasoconstriction through Cyp4a in the mouse aorta. Adenosine 5′- N-ethylcarboxamide (NECA; 10−6 M), an adenosine analog, caused relaxation in wild-type A2AAR (A2AAR+/+; +33.99 ± 4.70%, P < 0.05) versus contraction in A2AAR knockout (A2AAR−/−; −27.52 ± 4.11%) mouse aortae. An A2AAR-specific antagonist (SCH-58261; 1μM) changed the NECA (10−6 M) relaxation response to contraction (−35.82 ± 4.69%, P < 0.05) in A2AAR+/+ aortae, whereas no effect was noted in A2AAR−/− aortae. Significant contraction was seen in the absence of the endothelium in A2AAR+/+ (−2.58 ± 2.25%) aortae compared with endothelium-intact aortae. An endothelial nitric oxide synthase inhibitor ( N-nitro-l-arginine methyl ester; 100 μM) and a cyclooxygenase inhibitor (indomethacin; 10 μM) failed to block NECA-induced relaxation in A2AAR+/+ aortae. A selective inhibitor of CYP epoxygenases (methylsulfonyl-propargyloxyphenylhexanamide; 10 μM) changed NECA-mediated relaxation (−22.74 ± 5.11% at 10−6 M) and CGS-21680-mediated relaxation (−18.54 ± 6.06% at 10−6 M) to contraction in A2AAR+/+ aortae, whereas no response was noted in A2AAR−/− aortae. Furthermore, an epoxyeicosatrienoic acid (EET) antagonist [14,15-epoxyeicosa-5( Z)-enoic acid; 10 μM] was able to block NECA-induced relaxation in A2AAR+/+ aortae, whereas ω-hydroxylase inhibitors (10 μM dibromo-dodecenyl-methylsulfimide and 10 μM HET-0016) changed contraction into relaxation in A2AAR−/− aorta. Cyp2c29 protein was upregulated in A2AAR+/+ aortae, whereas Cyp4a was upregulated in A2AAR−/− aortae. Higher levels of dihydroxyeicosatrienoic acids (DHETs; 14,15-DHET, 11,12-DHET, and 8,9-DHET, P < 0.05) were found in A2AAR+/+ versus A2AAR−/− aortae. EET levels were not significantly different between A2AAR+/+ and A2AAR−/− aortae. It is concluded that CYP epoxygenases play an important role in A2AAR-mediated relaxation, and the deletion of the A2AAR leads to contraction through Cyp4a.

ACh dilates pial arterioles in endothelial and neuronal NOS knockout mice by NO-dependent mechanisms

1996 ◽  
Vol 271 (3) ◽  
pp. H1145-H1150 ◽  
Author(s):  
W. Meng ◽  
J. Ma ◽  
C. Ayata ◽  
H. Hara ◽  
P. L. Huang ◽  
...  
Keyword(s):  
Mutant Mice ◽  
Mouse Strains ◽  
Wild Type ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Neuronal Nos ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Dose Dependent

We used mice with deletions in either the endothelial nitric oxide synthase (eNOS) or neuronal NOS (nNOS) gene to investigate the role of eNOS and nNOS in acetylcholine (ACh)-induced relaxation of pial arterioles (20-30 microns). Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window, and NOS activity was determined by the conversion of [3H]arginine to [3H]citrulline in subjacent cortex. ACh superfusion (1, 10 microM) caused atropine-sensitive dose-dependent arteriolar dilation in all three mouse strains. At 10 microM, increases of 20 +/- 2, 31 +/- 3, and 23 +/- 3% were recorded in wild-type (n = 25), nNOS mutant (n = 15), and eNOS mutant (n = 20) mice, respectively. NG-nitro-L-arginine (L-NNA, 1 mM) superfusion inhibited cortical NOS activity by > 70% and abrogated the response in wild-type mice while blocking the dilation by approximately 50% in eNOS mutant and nNOS mutant mice. Only in the eNOS mutant did tetrodotoxin (TTX) superfusion (1 microM) attenuate ACh-induced dilation (n = 6). The residual dilation after L-NNA in eNOS mutant mice could be blocked completely by TTX-plus L-NNA. Our findings indicate that 1) ACh dilates pial arterioles of wild-type mice by NOS-dependent mechanisms as reported in other species, 2) the response in nNOS mutant mice resembles the wild-type response except for enhanced dilation to ACh and reduced L-NNA sensitivity, and 3) surprisingly, the response in eNOS mutant mice is partially NOS dependent and attenuated by both TTX and L-NNA. Because nNOS is constitutively expressed in eNOS mutants, these findings coupled with the TTX results suggest that an nNOS-dependent mechanism may compensate for the chronic loss of eNOS activity after targeted gene disruption.

scholarly journals Role of Endothelial Nitric Oxide Synthase in Isoflurane Conditioning‐Induced Neurovascular Protection in Subarachnoid Hemorrhage

2020 ◽  
Vol 9 (20) ◽  
Author(s):  
Umeshkumar Athiraman ◽  
Keshav Jayaraman ◽  
Meizi Liu ◽  
Tusar Giri ◽  
Jane Yuan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Nitric Oxide Synthase ◽  
Delayed Cerebral Ischemia ◽  
Neurological Deficits ◽  
Wild Type ◽  
Neurovascular Protection ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Background Delayed cerebral ischemia remains a common and profound risk factor for poor outcome after subarachnoid hemorrhage (SAH). The aim of our current study is to define the role of endothelial nitric oxide synthase (eNOS) in isoflurane conditioning‐induced neurovascular protection after SAH. Methods and Results Ten‐ to 14‐week‐old male wild‐type mice (C57BL/6) as controls and eNOS knockout male mice (strain # 002684) were obtained for the study. Animals underwent either sham surgery, SAH surgery, or SAH with isoflurane conditioning. Anesthetic post conditioning was performed with isoflurane 2% for 1 hour, 1 hour after SAH. Normothermia was maintained with the homeothermic blanket. In a separate cohort, nitric oxide synthase was inhibited by a pan nitric oxide synthase inhibitor, L‐nitroarginine methyl ester. Vasospasm measurement was assessed 72 hours after SAH and neurological function was assessed daily. Isoflurane‐induced changes in the eNOS protein expression were measured. eNOS protein expression was significantly increased by isoflurane conditioning in naïve mice as well as mice subjected to SAH. Vasospasm of the middle cerebral artery and neurological deficits were evident following SAH versus sham surgery, both in wild‐type mice and eNOS knockout mice. Isoflurane conditioning attenuated vasospasm and neurological deficits in wild‐type mice. This delayed cerebral ischemia protection was lost in L‐nitroarginine methyl ester ‐administered mice and eNOS knockout mice. Conclusions Our data indicate isoflurane conditioning provides robust protection against SAH‐induced vasospasm and neurological deficits, and that this delayed cerebral ischemia protection is critically mediated via isoflurane‐induced augmentation of eNOS.

scholarly journals Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

2014 ◽  
Vol 306 (8) ◽  
pp. H1146-H1153 ◽  
Author(s):  
Dong Sun ◽  
Azita J. Cuevas ◽  
Katherine Gotlinger ◽  
Sung Hee Hwang ◽  
Bruce D. Hammock ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Epoxyeicosatrienoic Acids ◽  
Myogenic Response ◽  
Lower Blood Pressure ◽  
Lower Blood ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via cytochrome P450 (CYP)/epoxygenases. EETs possess cardioprotective properties and are catalyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs) that lack vasoactive property. To date, the role of sEH in the regulation of myogenic response of resistant arteries, a key player in the control of blood pressure, remains unknown. To this end, experiments were conducted on sEH-knockout (KO) mice, wild-type (WT) mice, and endothelial nitric oxide synthase (eNOS)-KO mice treated with t-TUCB, a sEH inhibitor, for 4 wk. sEH-KO and t-TUCB-treated mice displayed significantly lower blood pressure, associated with significantly increased vascular EETs and ratio of EETs/DHETs. Pressure-diameter relationships were assessed in isolated and cannulated gracilis muscle arterioles. All arterioles constricted in response to increases in transmural pressure from 60 to 140 mmHg. The myogenic constriction was significantly reduced, expressed as an upward shift of pressure-diameter curve, in arterioles of sEH-KO and t-TUCB-treated eNOS-KO mice compared with their controls. Removal of the endothelium, or treatment of the vessels with PPOH, an inhibitor of EET synthase, restored the attenuated pressure-induced constriction to the levels similar to those observed in their controls but had no effects on control vessels. No difference was observed in the myogenic index, or in the vascular expression of eNOS, CYP2C29 (EET synthase), and CYP4A (20-HETE synthase) among these groups of mice. In conclusion, the increased EET bioavailability, as a function of deficiency/inhibition of sEH, potentiates vasodilator responses that counteract pressure-induced vasoconstriction to lower blood pressure.

scholarly journals Regulation of miRNAs by Natural Antioxidants in Cardiovascular Diseases: Focus on SIRT1 and eNOS

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 377
Author(s):  
Yunna Lee ◽  
Eunok Im
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Natural Antioxidants ◽  
Sirtuin 1 ◽  
Potential Benefits ◽  
New Perspective ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality worldwide. The potential benefits of natural antioxidants derived from supplemental nutrients against CVDs are well known. Remarkably, natural antioxidants exert cardioprotective effects by reducing oxidative stress, increasing vasodilation, and normalizing endothelial dysfunction. Recently, considerable evidence has highlighted an important role played by the synergistic interaction between endothelial nitric oxide synthase (eNOS) and sirtuin 1 (SIRT1) in the maintenance of endothelial function. To provide a new perspective on the role of natural antioxidants against CVDs, we focused on microRNAs (miRNAs), which are important posttranscriptional modulators in human diseases. Several miRNAs are regulated via the consumption of natural antioxidants and are related to the regulation of oxidative stress by targeting eNOS and/or SIRT1. In this review, we have discussed the specific molecular regulation of eNOS/SIRT1-related endothelial dysfunction and its contribution to CVD pathologies; furthermore, we selected nine different miRNAs that target the expression of eNOS and SIRT1 in CVDs. Additionally, we have summarized the alteration of miRNA expression and regulation of activities of miRNA through natural antioxidant consumption.

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