Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy

Abstract

Hypertension remains the leading cause of disease burden worldwide. Hypertension can originate in the early stages of life. A growing body of evidence suggests that oxidative stress, which is characterized as a reactive oxygen species (ROS)/nitric oxide (NO) disequilibrium, has a pivotal role in the hypertension of developmental origins. Results from animal studies support the idea that early-life oxidative stress causes developmental programming in prime blood pressure (BP)-controlled organs such as the brain, kidneys, heart, and blood vessels, leading to hypertension in adult offspring. Conversely, perinatal use of antioxidants can counteract oxidative stress and therefore lower BP. This review discusses the interaction between oxidative stress and developmental programming in hypertension. It will also discuss evidence from animal models, how oxidative stress connects with other core mechanisms, and the potential of antioxidant therapy as a novel preventive strategy to prevent the hypertension of developmental origins.

Keywords: antioxidant; asymmetric dimethylarginine; developmental origins of health and disease (DOHaD); hypertension; nitric oxide; oxidative stress; reactive oxygen species; renin-angiotensin system.

Figure 1

Schema outlining how early-life environmental insults induce hypertension in later life via oxidative stress programming of various organ systems and regulatory hormones. Early-life insults cause an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO). ROS are derived from enzymes that produce superoxide radical (O₂⁻) intracellularly, such as NADPH oxidase and xanthine oxidase. Excessive ROS can be offset by the action of antioxidant enzymes. The components of the antioxidant defense are superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (Cat), etc. Nitric oxide synthase (NOS) catalyzes l-arginine to produce NO. NO mediates vasodilation and opposes vasoconstrictor effects driven by ROS. Uncoupled NOS produces superoxide, which scavenges NO, leading to peroxynitrite (ONOO⁻) formation. Oxidative stress is a condition where ROS overwhelm the antioxidant system, leading to cellular injury in the form of damaged DNA, lipids, and proteins. During development, oxidative stress triggers the developmental programming of prime organs involved in the regulation of blood pressure (i.e., heart, kidneys, brain, and blood vessels) and regulatory hormones, leading to hypertension in later life.

Figure 2

Oxidative stress and possible molecular pathways linked to the hypertension of developmental origins.

Figure 3

Schema outlining the potential antioxidants as a reprogramming strategy to prevent the hypertension of developmental origins.