Melatonin improves endothelial function in vitro and prolongs pregnancy in women with early-onset preeclampsia

J Pineal Res. 2018 May 16:e12508. doi: 10.1111/jpi.12508. [Epub ahead of print]

Melatonin improves endothelial function in vitro and prolongs pregnancy in women with early-onset preeclampsia.

Hobson SR1,2,3,4,  Gurusinghe S3, Lim R1,3, Alers NO3,  Miller SL1,3, Kingdom JC4, Wallace EM1,3.

Author information

1
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, 3168, Australia.
2
Women’s Health Program, Monash Health, Clayton, Victoria, 3168, Australia.
3
The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, 3168, Australia.
4
Department of Obstetrics and Gynaecology, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Abstract

Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. There have been no material advances in the treatment of preeclampsia for nearly 50 years. Combining in vitro studies and a clinical trial, we aimed to determine if melatonin could be a useful adjuvant therapy. In a xanthine/xanthine oxidase (X/XO) placental explant model, melatonin reduced oxidative stress (8-isoprostane) and enhanced antioxidant markers (Nrf2 translocation, HO-1), but did not affect explant production of anti-angiogenic factors (sFlt, sEng, activin A). In cultured HUVECs, melatonin mitigated TNF?-induced vascular cell adhesion molecule expression and rescued the subsequent disruption to endothelial monolayer integrity but did not affect other markers for endothelial activation and dysfunction. In a phase I trial of melatonin in 20 women with preeclampsia we assessed the safety and efficacy of melatonin on (i) preeclampsia progression, (ii) clinical outcomes and (iii) oxidative stress, matching outcomes with recent historical controls receiving similar care. Melatonin therapy was safe for mothers and their fetuses. Compared to controls, melatonin administration extended the mean ±SEM diagnosis to delivery interval by 6 ± 2.3 days reduced the need for increasing antihypertensive medication on days 3-4 (13% vs 71%), days 6-7 (8% vs 51%) and at delivery (26% vs 75%). All other clinical and biochemical measures  of disease severity were unaffected by melatonin. We have shown that melatonin has the potential to mitigate maternal endothelial pro-oxidant injury and could therefore provide effective adjuvant therapy to extend pregnancy duration to deliver improved clinical outcomes for women with severe preeclampsia. This article is protected by copyright. All rights reserved.

KEYWORDS:

endothelial cell; hypertension; melatonin; placenta; preeclampsia; pregnancy

Int J Cardiol. 2018 Jul 15;263:111-117.

Circulating metabolites of strawberry mediate reductions in vascular inflammation and endothelial dysfunction in db/db mice.

Petersen C1, Bharat D1, Cutler BR1, Gholami S1,  Denetso C1, Mueller JE1, Cho JM1, Kim JS1, Symons JD2,  Anandh Babu PV3.

Author information

1
Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT 84112, USA.
2
Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT 84112, USA; Division of Endocrinology, Metabolism, and Diabetes; and Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
3
Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: anandh.velayutham@utah.edu.

Abstract

BACKGROUND:

Cardiovascular disease is 2-4-fold more prevalent in patients with diabetes. Human studies support the cardiovascular benefits of strawberry consumption but the effects of strawberry on diabetic vasculature are unknown. We tested the hypothesis that dietary strawberry supplementation attenuates vascular inflammation and dysfunction in diabetic mice.

METHODS:

Seven-week-old diabetic db/db mice that consumed standard diet (db/db) or diet supplemented with 2.35% freeze-dried strawberry (db/db?+?SB) for ten weeks were compared to non-diabetic control mice (db/+). Indices of vascular inflammation and dysfunction were measured. Endothelial cells (ECs) were isolated from the vasculature to determine the influence of strawberry on them. The effect of metabolites of strawberry on endothelial inflammation was determined by incubating mouse aortic ECs (MAECs) with ±5% serum, obtained from strawberry fed mice (metabolites serum) or standard diet fed mice (control serum)?±?25?mM glucose and 100??M palmitate.

RESULTS:

db/db mice exhibited an increased monocyte binding to vessel, elevated blood pressure, and reduced endothelial-dependent vasorelaxation compared with db/+ mice but each defect was attenuated in db/db?+?SB mice. The elevation of inflammatory molecules, NOX2 and inhibitor-?B kinase observed in ECs from db/db vs. db/+ mice was suppressed in db/db?+?SB mice. Glucose and palmitate increased endothelial inflammation in MAECs but were normalized by co-incubation with metabolites serum.

CONCLUSIONS:

Dietary supplementation of strawberry attenuates indices of vascular inflammation and dysfunction in diabetic db/db mice. The effect of strawberry on vasculature is endothelial-dependent and possibly mediated through their circulating metabolites. Strawberry might complement conventional therapies to improve vascular complications in diabetics.

KEYWORDS:

Diabetes; Endothelial dysfunction; Metabolites; Strawberry; Vascular inflammation

Exp Physiol. 2018 Apr 30. doi: 10.1113/EP087002. [Epub ahead of print]

Vasomotion as an oscillatory sign of functional impairment in the human internal thoracic artery: A study based on risk factors and vessel reactivity.

Fonseca DA1,2,3, Antunes PE4,  Antunes MJ4, Cotrim MD1,2,3.

Author information

1
Laboratory of Pharmacology and Pharmaceutical Care, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
2
Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
3
CNC.iCBR, University of Coimbra, Coimbra, Portugal.
4
Centre of Cardiothoracic Surgery, University Hospital and Faculty of Medicine of Coimbra, Coimbra, Portugal.

Abstract

NEW FINDINGS:

What is the central question of this study? Vasomotion has been viewed as a rhythmic oscillation of the vascular tone that is physiologically important for optimal tissue perfusion. Also, it has been primarily studied in the microcirculation. However, the precise underlying mechanisms and the physiological significance remain unknown. What is the main finding and its importance? Vasomotion is not specific of the microcirculation, as shown by our findings. In human arteries from patients undergoing cardiac surgery, an increased incidence was associated with endothelial dysfunction settings. Therefore, this oscillatory behaviour may be a signal of functional impairment and not of integrity.

ABSTRACT:

Vasomotion has been defined as the rhythmic oscillation of the vascular tone, involved in the control of the blood flow and subsequently tissue perfusion. Our aims were to study the incidence in the human internal thoracic artery and the correlation of this phenomenon with the clinical profile and parameters of vascular reactivity. In our study, vasomotion was elicited with a single-dose contractile stimulation of norepinephrine (10 ?M) in internal thoracic artery segments, from patients undergoing coronary artery bypass grafting, mounted in tissue organ bath chambers. The incidence was 29.1%. Vessel samples with vasomotion presented significantly higher contractility both to potassium chloride (Emax  of 7.65 ± 5.81 mN vs. 4.52 ± 3.73 mN in control, p = 0.024) and norepinephrine (Emax  of 7.60 ± 5.93 mN vs. 2.96 ± 4.41 mN in control, p < 0.001). Predictive modelling through multivariable logistic regression analysis showed that female sex (odds ratio = 9.82) and increasing maximal response to norepinephrine (odds ratio = 1.19, per 1-mN increase) were associated with higher probability of the occurrence of vasomotion, whereas increasing kidney function (expressed as estimated glomerular filtration rate) was associated with a lower probability (odds ratio = 0.97, per 1-mL/min/1.73 m2  ). Our results provide a characterization of the vasomotion phenomenon in the internal thoracic artery and suggest that vasomotion may be associated with endothelial dysfunction settings, as determined by a multivariable analysis approach. Considering the associations observed in our results, vasomotion may be a signal of functional impairment and not of integrity. This article is protected by copyright. All rights reserved.

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