Abstract P224: Cyclooxygenase-dependent Mechanisms Mediate In Part The Anti-dilatory Effects Of Uterine Perivascular Adipose Tissue In Rat Pregnancy

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Oluwatobiloba OSIKOYA ◽  
Spencer C Cushen ◽  
Styliani Goulopoulou
Keyword(s):  
Adipose Tissue ◽  
Physiological Salt Solution ◽  
Response Curves ◽  
Pregnant Rats ◽  
Perivascular Adipose Tissue ◽  
Uterine Arteries ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Relaxation Responses ◽  
Cox 1

Introduction: Uterine perivascular adipose tissue (PVAT) contributes to uterine blood flow regulation in pregnancy, at least in part, due to its effects on uterine artery tone. We hypothesized that the anti-dilatory effects of uterine PVAT are mediated by vascular nitric oxide synthase (NOS)- and cyclooxygenase (COX)-dependent mechanisms. Methods: Main uterine arteries from pregnant and non-pregnant rats were mounted onto a wire myograph. Concentration-response curves to acetylcholine (ACh, 10 -9 - 3x10 -5 M) were performed on arteries exposed to physiological salt solution or PVAT-conditioned media (PVAT media ) in the presence of the following inhibitors: a) L-NAME (NOS inhibitor, 100 μM), b) indomethacin (COX inhibitor, 10 μM), c) SC560 (COX-1 inhibitor, 1 μM), d) NS398 (COX-2 inhibitor, 1 μM)]. Results: NOS inhibition abolished ACh-induced relaxation in uterine arteries from pregnant rats and exposure to PVAT media did not change this effect [AUC, (-)PVAT media : 244.6 ± 18.1 vs. (-)PVAT media /(+)L-NAME: 52.64 ± 7.4, p < 0.0001; (+)PVAT media : 202.4 ± 15.5 vs. (+)PVAT media /(+)L-NAME: 56.17 ± 11.3, p < 0.0001]. Indomethacin suppressed ACh-induced relaxation in uterine arteries from pregnant rats [AUC, (-)PVAT media : 243.6 ± 6.6 vs. (-)PVAT media /(+)Indomethacin: 123.6 ± 12.3, p < 0.0001] but not in non-pregnant rats (p>1.0). In arteries incubated with PVAT media , the presence of indomethacin increased ACh-induced relaxation [AUC, (+)PVAT media : 125.2 ± 11.4 vs. (+)PVAT media /(+)Indomethacin: 179.1 ± 14.7, p = 0.01]. COX-1 but not COX-2 inhibition suppressed relaxation responses to ACh [AUC, COX-1 inhibition, (-)PVAT media : 244.6 ± 12.0 vs. (-)PVAT media /(+)SC560: 142.4 ± 15.4, p = 0.02; COX-2 inhibition, (-)PVAT media vs. (-)PVAT media /(+)NS398, p=0.1). The anti-dilatory effects of PVAT were not observed in the presence of SC560 or NS398 (p>0.05). Exposure to PVAT media increased the protein content of COX-1 (p=0.05) and COX-2 (p=0.03) and the production of thromboxane B 2 (p=0.01) in uterine arteries from pregnant rats. Conclusion: The anti-dilatory effects of PVAT-derived factors on uterine arteries are mediated in part by COX-derived products and this mechanism is specific to pregnancy.

scholarly journals Cyclooxygenase-dependent mechanisms mediate in part the anti-dilatory effects of perivascular adipose tissue in uterine arteries from pregnant rats

2021 ◽  
Author(s):  
Oluwatobiloba Osikoya ◽  
Spencer C. Cushen ◽  
Styliani Goulopoulou
Keyword(s):  
Adipose Tissue ◽  
Selective Inhibition ◽  
Response Curves ◽  
Pregnant Rats ◽  
Perivascular Adipose Tissue ◽  
Uterine Arteries ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Relaxation Responses ◽  
Cox 1

AbstractUterine perivascular adipose tissue (PVAT) contributes to uterine blood flow regulation in pregnancy, at least in part, due to its effects on uterine artery reactivity. Here, we investigated the effects of uterine PVAT on endothelium-dependent pathways involved in relaxation of main uterine arteries. We hypothesized that uterine PVAT modulates the balance between the contribution of nitric oxide synthase (NOS)- and cyclooxygenase (COX)-dependent pathways to acetylcholine (ACh)-induced relaxation in isolated uterine arteries. Concentration-response curves to ACh (1 nM – 30 µM) were performed on main uterine arteries from pregnant and non-pregnant rats. Arteries were exposed to Krebs-Henseleit solution (control) or PVAT-conditioned media (PVATmedia) in the presence of the following inhibitors: L-NAME (100 µM), indomethacin (COX inhibitor, 10 µM), SC560 (selective COX-1 inhibitor, 1 µM), NS398 (selective COX-2 inhibitor, 1 µM), SQ 29,548 (selective thromboxane receptor (TP) inhibitor, 1 µM). Indomethacin suppressed ACh-induced relaxation in control uterine arteries from pregnant rats (p<0.0001) but not in non-pregnant rats (p>1.0). In arteries incubated with PVATmedia, the presence of indomethacin increased ACh-induced relaxation, reversing the anti-dilatory effect of PVATmedia. NOS inhibition reduced ACh-induced relaxation in uterine arteries from pregnant rats, and exposure to PVATmedia did not change this effect. Selective inhibition of COX-1 but not COX-2 suppressed relaxation responses to ACh in control arteries. The presence of PVATmedia abolished the effect COX-1 inhibition. Incubation of uterine arteries from pregnant rats with PVATmedia increased production of thromboxane B2 (TxB2, p=0.01). TP inhibition did not have any effect on the anti-dilatory properties of PVATmedia. In conclusion, uterine PVAT releases transferable factors that reduce relaxation responses to ACh via a COX-dependent mechanism in isolated uterine arteries from pregnant rats.

Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

1999 ◽  
Vol 276 (3) ◽  
pp. R913-R921 ◽  
Author(s):  
Ronald I. Clyman ◽  
Pierre Hardy ◽  
Nahid Waleh ◽  
Yao Qi Chen ◽  
Françoise Mauray ◽  
...  
Keyword(s):  
Significant Role ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Fetal Lamb ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

Abstract P499: Protein Kinase Cα Deletion Causes Hypotension Due to Decreased Vascular Contractility

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Brandi M Wynne ◽  
Cameron G McCarthy ◽  
Theodora Szasz ◽  
Janet D Klein ◽  
R. Clinton Webb ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Contractility ◽  
Mesenteric Arteries ◽  
Response Curves ◽  
Smooth Muscle Contractility ◽  
Vascular Contractility ◽  
Cox Inhibitor ◽  
Protein Kinase Cα ◽  
Multiple Cell ◽  
Relaxation Responses

Protein kinase Cα (PKCα) regulates multiple cell signaling pathways, including those that impact blood pressure. PKCα activation increases vascular smooth muscle contractility, yet reduces cardiac contractility. PKCα has also been shown to modulate nephron ion transport. We have shown that PKCα deletion leads to hypotension, with compensatory increases in sodium retention. Here, we hypothesized that PKCα deficiency reduces vascular contractility, leading to decreased mean arterial pressure (MAP). MAP, measured by telemetry, was decreased in PKC KO (≈12 mmHg) compared to PKC control (PKC CTL) mice. Aorta and mesenteric arteries were isolated, and concentration response curves (CRCs) to phenylephrine (Phe), acetylcholine (ACh) or sodium nitroprusside (SNP) were performed in the presence of vehicle or the following inhibitors: L-NAME or indomethacin (NOS, COX inhibitor, resp. ). CRCs to KCL were performed to assess receptor-independent vascular responses. In aorta, we observed a striking reduction in KCl-mediated contraction (5.8±0.3mN vs. 10.4±1.1mN control, **p<0.01). PKC KO aorta and mesenteric arteries had decreased contractile responses to Phe, as compared to control (aorta, 12.7±0.5mN R max vs. 16.3±0.5mN R max , and mesenteric 9.9±0.3mN R max vs. 11.8±0.6mN R max ; n=4, **p<0.01), revealing a role for reduced vascular contractility. Endothelium-mediated relaxation responses to ACh were also increased in PKC KO mice, as compared to control (59.3±6.8% R max vs. 45.4±3.2% R max , n=4, *p<0.05). Interestingly, NOS inhibition increased contractility in mesenteric arteries from PKC KO mice (8.55±2.65mN R max vs. 6.95±0.39mN R max control, n=4, ***p<0.001). However, PKC KO aorta had an enhanced response to COX inhibition (12.2±0.7mN R max vs. 10.1±0.6mN R max control, n=4, *p<0.05) suggesting that PKCα may be negatively regulating NOS in mesenteric arteries, and COX-mediated prostaglandin production in the aorta. No differences were observed in the relaxation responses to SNP. These data suggest that global deletion of PKCα results in hypotension due to decreased vascular contractility, and loss of PKCα-mediated inhibition of endothelial relaxing factors. Thus, systemic targeting of PKCα may be beneficial for the reduction of MAP.

scholarly journals Changes in the sensitivity to glucagon of lipolysis in adipocytes from pregnant and lactating rats

1988 ◽  
Vol 254 (3) ◽  
pp. 661-665 ◽  
Author(s):  
V A Zammit
Keyword(s):  
Adipose Tissue ◽  
The Other ◽  
High Concentration ◽  
Response Curves ◽  
Pregnant Rats ◽  
Adipose Tissue Lipolysis ◽  
The Right ◽  
Peak Lactation ◽  
Stimulation Of

1. Rates of lipolysis were measured at different concentrations of glucagon in adipocytes prepared from parametrial adipose tissue of fed or starved rats in different reproductive states. All experiments were performed in the presence of a high concentration of adenosine deaminase (1 unit/ml). 2. Maximal rates of lipolysis (elicited by 25 nM-glucagon in each instance) were higher in adipocytes from peak-lactating rats than those from pregnant animals in both the fed and starved states. 3. Of adipocytes from fed animals, those from peak-lactating rats were the most sensitive to glucagon, whereas those from late-pregnant and early-lactating rats were 1-2 orders of magnitude less sensitive. 4. Adipocytes from 24 h-starved rats showed a much smaller stimulation of lipolysis by glucagon, making the assessment of sensitivity difficult. Therefore, rates of lipolysis were also measured in the presence of a maximally anti-lipolytic dose of insulin. The presence of insulin did not alter the relative sensitivities to glucagon of adipocytes from fed animals in different reproductive states, although all dose-response curves were shifted to the right. When lipolysis in adipocytes from starved animals was measured in the presence of insulin, it became evident that starvation for 24 h markedly increased the sensitivity of adipocytes from late-pregnant rats to glucagon, but did not affect that of cells from animals in the other reproductive states. 5. It is concluded that the large changes in sensitivity to glucagon that occurred during the reproductive cycle may enable the modulation of adipose-tissue lipolysis in vivo to satisfy the different metabolic requirements of the animal in the transition from pregnancy to peak lactation.

scholarly journals Interaction of Perivascular Adipose Tissue and Sympathetic Nerves in Arteries From Normotensive and Hypertensive Rats

2016 ◽  
pp. S391-S399 ◽  
Author(s):  
J. TÖRÖK ◽  
A. ZEMANČÍKOVÁ ◽  
Z. KOCIANOVÁ
Keyword(s):  
Adipose Tissue ◽  
Electrical Stimulation ◽  
Mesenteric Artery ◽  
Sympathetic Nerves ◽  
Mesenteric Arteries ◽  
Inhibitory Influence ◽  
Hypertensive Rats ◽  
Response Curves ◽  
Perivascular Adipose Tissue ◽  
Endogenous Noradrenaline

The inhibitory action of perivascular adipose tissue (PVAT) in modulation of arterial contraction has been recently recognized and contrasted with the prohypertensive effect of obesity in humans. In this study we demonstrated that PVAT might have opposing effect on sympatho-adrenergic contractions in different rat conduit arteries. In superior mesenteric artery isolated from normotensive Wistar-Kyoto rats (WKY), PVAT exhibited inhibitory influence on the contractions to exogenous noradrenaline as well as to endogenous noradrenaline released from arterial sympathetic nerves during transmural electrical stimulation or after application of tyramine. In contrast, the abdominal aorta with intact PVAT responded with larger contractions to transmural electrical stimulation and tyramine when compared to the aorta after removing PVAT; the responses to noradrenaline were similar in both. This indicates that PVAT may contain additional sources of endogenous noradrenaline which could be responsible for the main difference in the modulatory effect of PVAT on adrenergic contractions between abdominal aortas and superior mesenteric arteries. In spontaneously hypertensive rats (SHR), the anticontractile effect of PVAT in mesenteric arteries was reduced, and the removal of PVAT completely eliminated the difference in the dose-response curves to exogenous noradrenaline between SHR and WKY. These results suggest that in mesenteric artery isolated from SHR, the impaired anticontractile influence of PVAT might significantly contribute to its increased sensitivity to adrenergic stimuli.

Key role for cyclooxygenase-2 in PGE2 and PGF2α receptor regulation and cerebral blood f low of the newborn

1997 ◽  
Vol 273 (4) ◽  
pp. R1283-R1290 ◽  
Author(s):  
Ding-You Li ◽  
Pierre Hardy ◽  
Daniel Abran ◽  
Ana-Katherine Martinez-Bermudez ◽  
Anne-Marie Guerguerian ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Agonist ◽  
Prostaglandin E ◽  
Receptor Density ◽  
Cerebral Vasculature ◽  
Newborn Brain ◽  
Cox Inhibitor ◽  
Newborn Pigs ◽  
Cox 2 ◽  
Cox 1

Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E2(PGE2) and PGF2α receptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evidence that COX-2-generated prostaglandins govern PGE2 and PGF2α receptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE2 and PGF2α receptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE2 and PGF2α concentrations were significantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS-398, and ibuprofen, PGE2 and PGF2α receptor densities in brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE2(EP1 receptor agonist), M&B-28767 (EP3 receptor agonist), PGF2α, and fenprostalene (PGF2αanalog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure limit of cerebral cortex and periventricular blood flow autoregulation from 85 to ≥125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE2 and PGF2α receptors, IP3 production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE2 and PGF2α receptors and their functions in the newborn cerebral vasculature.

scholarly journals Vasorelaxing effects of estetrol in rat arteries

2012 ◽  
Vol 215 (1) ◽  
pp. 97-106 ◽  
Author(s):  
Rob H P Hilgers ◽  
Suzanne Oparil ◽  
Wout Wouters ◽  
Herjan J T Coelingh Bennink
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Soluble Guanylate Cyclase ◽  
Ex Vivo ◽  
Response Curves ◽  
Uterine Arteries ◽  
17Β Estradiol ◽  
Pharmacological Blockade ◽  
Relaxation Responses

This study comparedex vivorelaxing responses to the naturally occurring human hormone estetrol (E4) vs 17β-estradiol (E2) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRCs) to E4and E2(0.1–100 μmol/l) were constructed. In all arteries tested, E4had lower potency than E2, although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182 780 (1 μmol/l) caused a significant rightward shift in the CRC to both E4and E2, indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases byNω-nitro-l-arginine methyl ester (l-NAME) blunted E2-mediated but not E4-mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E4or E2in uterine arteries. Combined blockade of NO release and action withl-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E4compared with E2in uterine arteries. Endothelium denudation inhibited responses to both E4and E2, while E4and E2concentration-dependently blocked smooth muscle cell Ca2+entry in K+-depolarized and Ca2+-depleted uterine arteries. In conclusion, E4relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E4-induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca2+entry, but not NO synthases or endothelium-dependent hyperpolarization.

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