Circadian rhythm and the molecular clock in endothelial function of the cardiovascular system.

All living organisms on Earth have evolved an internal, self‑sustained circadian rhythm that enables them to anticipate daily environmental changes driven by the 24‑hour rotation of our planet. However, modern lifestyle disruptions, including increased competitiveness and excessive work pressure, significantly disturb circadian rhythms and sleep-wake cycles, contributing to various diseases and posing a major public health concern. Cardiovascular disease (CVD) is a highly prevalent condition and the leading cause of death worldwide. Acute CVD events exhibit distinct diurnal patterns, occurring most frequently in the early morning after awakening and showing a secondary, smaller peak in the late afternoon. The endothelium, a single layer of cells lining the inner surface of blood vessels, is a key regulator of vascular homeostasis. Numerous clinical studies have observed that endothelial function shows diurnal oscillations, being lowest in the morning and highest at night, while circadian misalignment is associated with endothelial dysfunction. However, the underlying mechanisms remain poorly understood. In this review, we show that major circadian clock components play distinct roles in regulating endothelial function, particularly through the modulation of eNOS/NO pathway. In addition, conventional pathways involving inflammation, lipid metabolism, macrophage activity, and oxidative stress participate in the circadian regulation of endothelial physiology, although their precise mechanisms and the specific circadian clock elements involved remain unclear. These findings may help identify new pathways to reduce the global burden of endothelial dysfunction and its related diseases. Meanwhile, although governments and health organizations have recognized the strong link between disrupted circadian rhythms and human disease, and emphasized the need to incorporate circadian biology into clinical practice and public health strategies, much remains to be learned about how circadian rhythms regulate endothelial function and how circadian disruption induces endothelial dysfunction and associated disorders.