ESPE2021 ePoster Category 2 Sex differentiation, gonads and gynaecology or sex endocrinology (52 abstracts)
Vascular dysfunction and increased cardiovascular risk in hypospadias
Angela K Lucas-Herald 1,2 , Augusto C Montezano 1 , Rheure Alves-Lopes 1 , Laura Haddow 1 , Malika Alimussina 2 , Stuart O’Toole 3 , Martyn Flett 3 , Boma Lee 3 , S Basith Amjad 3 , Mairi Steven 3 , Katriona Brooksbank 1 , Linsay McCallum 1 , Christian Delles 1 , Sandosh Padmanabhan 1 , S Faisal Ahmed 2 & Rhian Touyz 1
1Institute of Cardiovascular and Medical Sciences, British Heart Foundation Centre for Research Excellence, University of Glasgow, Glasgow, United Kingdom; 2Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children, Glasgow, United Kingdom; 3Department of Paediatric Surgery, Royal Hospital for Children, Glasgow, United Kingdom
Background: Hypogonadism has been associated with cardiovascular disease. However, little is known about the cardiovascular impact of hypogonadism during development. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction during childhood and whether it is a risk factor for adult cardiovascular disease.
Methods: Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping (blood pressure, carotid intima-media thickness (CIMT), flow-mediated dilation, pulse wave velocity) was performed in 14 adolescents with hypospadias and 14 age-matched controls. Subcutaneous resistance arteries from penile skin from 27 young boys undergoing hypospadias repair and 37 age-matched controls were isolated and functional studies assessed by myography. Primary culture vascular smooth muscle cells (VSMCs) were used to assess: Rho kinase, redox signalling, nitric oxide (NO) and DNA damage. Systemic oxidative stress was assessed in plasma and urine (TBARS, 8-OHdG). Scottish linked hospital episode data identified 6,797 men with a history of hypospadias versus 8,073 controls matched for confounders.
Results: In adolescents with hypospadias, systolic blood pressure and pulse pressure were significantly increased, in association with increased CIMT SDS (1.6 vs 1.2, P < 0.05). Resistance arteries from boys with hypospadias demonstrated increased vasoconstriction (Emax: 137.9 vs 83.7, P < 0.001) and reduced endothelium-dependent (Emax: 77.3.4 vs 14.6, P < 0.0001) and endothelium-independent vasorelaxation (Emax: 39.5 vs 24.6, P < 0.0001). Hypercontractile responses were ameliorated by fasudil (Rho kinase inhibitor), NAC (ROS scavenger) and melittin (Nox5 inhibitor). Activation of pro-contractile signalling pathways (Rho kinase activity; myosin light chain phosphorylation) were increased in VSMCs from affected boys, associated with increased Nox5-induced ROS generation, oxidative stress and downregulation of NO and antioxidant pathways. Men with a history of hypospadias had a 3-fold higher risk of arrhythmia (OR [95% CI] 2.8[1.4-5.6], P < 0.001); 4-fold higher risk of hypertension (OR [95% CI] 4.2[1.5-11.9], P < 0.05) and 2-fold higher risk of heart failure (OR [95% CI] 1.9 [1.7-114.3], P < 0.05).
Conclusions: Hypospadias is associated with vascular dysfunction during childhood and predisposes to hypertension and cardiovascular disease in adulthood. Underlying vascular mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males.
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