Institute of Cardiovascular and Medical Sciences, British Heart Foundation Centre for Research Excellence, University of Glasgow, 126 University Avenue, Glasgow G12 8TA, UK.
Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children, 1345 Govan Road, Glasgow G45 8TF, UK.
Eur Heart J. 2022 May 14;43(19):1832-1845. doi: 10.1093/eurheartj/ehac112.
Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease.
Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5-11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7-114.3, P = 0.02).
Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying 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.
性腺功能减退与心血管疾病有关。然而，发育过程中性腺功能减退对心血管的影响尚不清楚。我们以尿道下裂作为性腺功能减退的替代指标，研究尿道下裂是否与血管功能障碍有关，以及是否是心血管疾病的危险因素。
本研究从分子机制到流行病学调查进行了全面研究。对尿道下裂患者和对照组的青少年进行临床血管表型分析。从接受尿道下裂修复术的男孩的阴茎皮肤中分离出小的皮下动脉，并通过肌动描记术评估其功能研究。血管平滑肌细胞用于评估：Rho 激酶、活性氧 (ROS)、一氧化氮合酶/一氧化氮和 DNA 损伤。通过血浆和尿液评估系统性氧化应激。比较有尿道下裂病史的男性和对照组的住院数据。在患有尿道下裂的青少年中，收缩压（P=0.005）、脉压（P=0.03）和颈动脉内膜-中层厚度标准差评分（P=0.01）升高。患有尿道下裂的男孩的动脉显示 U46619 诱导的血管收缩增加（P=0.009），乙酰胆碱诱导的内皮依赖性（P<0.0001）和硝普钠诱导的内皮非依赖性血管舒张减少（P<0.0001）。出生时患有尿道下裂的男性发生心律失常的风险增加[优势比（OR）2.8，95%置信区间（CI）1.4-5.6，P=0.003]；高血压（OR 4.2，95%CI 1.5-11.9，P=0.04）；和心力衰竭（OR 1.9，95%CI 1.7-114.3，P=0.02）。
尿道下裂与血管功能障碍有关，并导致成年后高血压和心血管疾病。潜在机制涉及受干扰的 Rho 激酶和 Nox5/ROS 依赖性信号。我们的新发现描绘了性腺功能减退症中血管损伤的分子机制，并确定尿道下裂是男性的心血管危险因素。
