SFEBES2018 Poster Presentations Reproduction (23 abstracts)
Altered vascular function in boys with hypospadias- role of reactive oxygen species
Angela Lucas Herald 1, , Rheure Alves-Lopes 1 , Laura Haddow 1 , Stuart O’Toole 3 , Syed Basith Amjad 4 , Martyn Flett 3 , Mairi Steven 3 , Boma Lee 3 , Augusto Montezano 1 , Syed Faisal Ahmed 2 & Rhian M. Touyz 1
1Institute for Cardiovascular and Medical Sciences, BHF Centre for Research Excellence, University of Glasgow, Glasgow, UK; 2Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK; 3Department of Paediatric Surgery, Royal Hospital for Children, Glasgow, UK, 4Department of Paediatric Surgery, Royal Hospital for Children, Bristol, UK.
Background: Hypospadias in boys may be associated with a lack of androgen exposure during the masculinisation programming window. As testosterone has effects on the vasculature, we assessed whether boys with hypospadias show evidence of vascular dysfunction.
Methods: Excess foreskin tissue was obtained from boys undergoing hypospadias repair (cases) or circumcision (controls) and small arteries dissected. Vascular contractility was assessed by wire myography in response to U46619 (thromboxane A2 analogue). Vascular smooth muscle cells (VSMCs) were cultured and generation of reactive oxygen species (ROS) was measured. NADPH oxidase (Nox) mRNA expression was measured by qPCR.
Results: 19 cases and 22 age-matched controls were enrolled in this study (median age 1.9 (range 1.3, 12.2) years). There were 8(42%) cases of distal, 4(21%) midshaft and 7(37%) proximal hypospadias. There was no underlying disorder of sex development in the cases and there were no differences in clinical cardiometabolic or biochemical parameters between the cases and controls. Arteries from cases demonstrated increased constriction to U46619 compared to controls (Emax: 175.6–66.3, P<0.001), an effect inhibited by the ROS scavenger N-acetylcysteine (NAC). VSMC superoxide anion (5.3 fold) production and H2O2 (3.3 fold) levels were increased in cases (P<0.05). Expression of Nox5, a major ROS-generating oxidase in VSMC, was also increased in cases (2.6 fold, P<0.05). Exposure of vessels to testosterone increased vasoconstriction to U46619 (Emax: 66.3 – 124.6 P<0.001) in controls, but not cases. Incubation with NAC abolished the testosterone-induced vascular effects. Vascular hypercontractility in boys with hypospadias was associated with reduced endothelium-dependent and independent vasorelaxation.
Conclusions: These novel data demonstrate that small arteries from boys with hypospadias exhibit increased vascular contractility and decreased vasorelaxation with associated increased Nox-derived ROS generation. The significance of vascular dysfunction in these boys is unclear, but may play a role in surgical outcome as well as altered long-term cardiovascular risk.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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