Red blood cell eNOS: a major player in regulating cardiovascular health.

Red blood cells (RBCs) have traditionally been seen as simple carriers of gases and nutrients in the body. One important non‐canonical function of RBCs in the cardiovascular system is the regulation of nitric oxide (NO) metabolism. It was shown that RBCs can scavenge NO, transport NO metabolites, and produce NO in hypoxic conditions, thereby inducing hypoxic vasodilation. RBCs also express an endothelial nitric oxide synthase (eNOS). However, its physiological significance has been controversial for many years. This review article provides a comprehensive overview of the experimental research on RBC eNOS signaling in vivo. These data show that RBC eNOS signaling modulates intracellular NO production and NO‐heme levels, as well as extracellular paracrine NO metabolite signaling, which contributes to regulating peripheral vascular resistance, blood pressure, and cardioprotection. Additionally, this article explores the potential intracellular molecular mechanisms and the implications of RBC eNOS in cardiovascular health and disease.