Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase

Area of Science:

• Vascular Biology
• Aging Research
• Endothelial Function

Background:

• Endothelium-dependent dilation (EDD) is crucial for vascular health and often declines with aging.
• Age-related vascular dysfunction is linked to imbalances in vasoconstrictor and vasodilator proteins.
• Endothelin-1 (ET-1) is a potent vasoconstrictor, while nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is a vasodilator.

Purpose of the Study:

• To investigate the association between aging, EDD, and the expression of key endothelial proteins like ET-1 and eNOS.
• To determine if increased vasoconstrictor or decreased vasodilator protein expression contributes to age-related EDD impairment.
• To explore the role of ET-1 signaling in age-related vascular dysfunction using a mouse model.

Main Methods:

• Collected endothelial cells (EC) from brachial arteries and peripheral veins of healthy young and older men (aged 18-78).
• Quantified protein expression using quantitative immunofluorescence for ET-1, serine 1177 phosphorylated eNOS (PeNOS), and total eNOS.
• Assessed EDD via forearm blood flow response to acetylcholine and flow-mediated dilation.
• Administered ET-1 receptor A antagonist (BQ-123) to aged mice to evaluate its effect on carotid artery dilation.

Main Results:

• Older men exhibited significantly lower EDD and higher ET-1 expression in brachial artery EC compared to younger men.
• EDD was inversely correlated with ET-1 expression in both brachial artery and venous EC.
• eNOS and PeNOS expression did not significantly decrease with age; eNOS even tended to increase.
• ET-1 receptor A inhibition partially restored acetylcholine-induced dilation in aged mice.

Conclusions:

• Increased ET-1 expression in vascular EC is a key factor contributing to age-related EDD impairment in healthy men.
• Reduced EDD with aging is primarily driven by altered ET-1 signaling, not by decreased eNOS expression or activity.
• ET-1 receptor A signaling plays a tonic suppressive role on EDD in aged individuals, as evidenced by mouse model studies.