Sarah B Withers1, Neha Passi1, Alfred S Williams1, Declan de Freitas2, Anthony M Heagerty1. 1. Cardiovascular Research Group, School of Biomedicine, University of Manchester, Manchester M13 9NT, UK. 2. Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester M13 9WL, UK.
Abstract
INTRODUCTION: The aim of this study was to investigate the effect of erythropoietin on vascular contractility using an in vitro model of hypoxia replicating the hypoxic environment of blood vessels and surrounding adipose tissue in obesity. METHODS AND RESULTS: Pharmacological in vitro studies were carried out on small mesenteric arterial segments from male Wistar rats with and without perivascular fat and endothelium. Contractile responses were investigated by wire myography under normoxia, experimental hypoxia ± erythropoietin and l-NNA. Perivascular fat exerted an anticontractile effect which was lost following the induction of experimental hypoxia. Erythropoietin prevented the loss of the anticontractile capacity when vessels were incubated for one hour before the induction of hypoxia or throughout the period of hypoxia; this was found to be independent of the function of perivascular fat, as fat denuded arteries had a similar reduction in contractility (artery no fat + hypoxia vs. artery no fat + hypoxia + erythropoietin). The mechanism by which erythropoietin was exerting its effect was found to be partially endothelium dependent and associated with an increase of nitric oxide bioavailability as nitric oxide synthase inhibition prevented the effect. CONCLUSIONS: Whilst erythropoietin is working downstream from perivascular fat, it is possible that it may be therapeutically useful in obesity when hypoxia and inflammation reduce the normal activity of perivascular fat.
INTRODUCTION: The aim of this study was to investigate the effect of erythropoietin on vascular contractility using an in vitro model of hypoxia replicating the hypoxic environment of blood vessels and surrounding adipose tissue in obesity. METHODS AND RESULTS: Pharmacological in vitro studies were carried out on small mesenteric arterial segments from male Wistar rats with and without perivascular fat and endothelium. Contractile responses were investigated by wire myography under normoxia, experimental hypoxia ± erythropoietin and l-NNA. Perivascular fat exerted an anticontractile effect which was lost following the induction of experimental hypoxia. Erythropoietin prevented the loss of the anticontractile capacity when vessels were incubated for one hour before the induction of hypoxia or throughout the period of hypoxia; this was found to be independent of the function of perivascular fat, as fat denuded arteries had a similar reduction in contractility (artery no fat + hypoxia vs. artery no fat + hypoxia + erythropoietin). The mechanism by which erythropoietin was exerting its effect was found to be partially endothelium dependent and associated with an increase of nitric oxide bioavailability as nitric oxide synthase inhibition prevented the effect. CONCLUSIONS: Whilst erythropoietin is working downstream from perivascular fat, it is possible that it may be therapeutically useful in obesity when hypoxia and inflammation reduce the normal activity of perivascular fat.
Entities:
Keywords:
ACh, acetylcholine; BMI, body mass index; CKD, chronic kidney disease; EPO, erythropoietin; KPSS, high potassium physiological salt solution; LDL, low density lipoproteins; Microcirculation; Myograph; NA, noradrenaline; NO, nitric oxide; Obesity; PSS, physiological salt solution; SEM, standard error of the mean; eNOS, endothelial nitric oxide synthase; l-NNA, Nω-nitro-l-arginine
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