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Figure 2. Mechanisms of Age-Associated Decline in NO Signaling and Its Contribution to Cardiovascular Dysfunction. [(A): Vasculature] In the vascular endothelium, aging-associated declines in eNOS activity and NO bioavailability are driven by reduced SIRT1 activity, elevated Cav-1 expression, and diminished Hsp90-eNOS interaction. Post-translational modifications - specifically, reduced phosphorylation at Ser1177 and increased phosphorylation at Thr495 - further suppress eNOS activity. Concurrently, age-related depletion of BH₄ levels promotes eNOS uncoupling, shifting its activity toward O₂^- production. The resulting reduction in NO bioavailability contributes to increased oxidative stress, mitochondrial dysfunction, and endothelial cell senescence. Collectively, these changes impair vascular function by promoting inflammation, reducing vasodilation, and attenuating angiogenesis. [(B) Myocardium] With advancing age, diminished NO bioavailability in the endothelium reduces paracrine signaling to cardiomyocytes, likely contributing to the downregulation of the cGMP-PKG pathway and, ultimately, diastolic dysfunction. This decline is further aggravated by the formation of peroxynitrite, generated from the interaction between nNOS-derived NO and O₂^-. In contrast, heightened β3-adrenergic receptor activity stimulates cardiomyocyte-associated eNOS-cGMP-PKG signaling, which leads to reduced inotropy, particularly at elevated heart rates, thus lowering cardiac reserve capacity. Plasmalemmal translocation of nNOS may further act to inhibit L-type calcium channels and negatively impact cardiac EC coupling, although this remains to be fully established. Together, age-associated declines in NO bioavailability in both the vascular endothelium and myocardium contribute to cardiovascular dysfunction and elevate the risk of life-threatening cardiovascular diseases. Created in BioRender. Patel, P. (2025) https://BioRender.com/v5hq0f8.