Endothelial cell‐specific reduction in mTOR ameliorates age‐related arterial and metabolic dysfunction

Abstract

Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age‐related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell‐specific deletion of mTOR reduced protein expression by 60–70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium‐dependent dilation (EDD) in old mice, indicating an improvement in age‐related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial‐rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development.

Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice

“…We have recently demonstrated that endothelial-specific reduction in mTOR improves age-related arterial and metabolic dysfunction. 13 Others have shown that EC-specific inactivation of a transcription factor, NF-κB, or tumor suppressor, p53, attenuates HF diet–induced metabolic dysfunction. 17,40 Reduction in inflammatory signals prevents obesity-induced impairments in the phosphorylation of Akt and eNOS.…”

“…17 In a recent study, we have found that endothelial mTOR (mammalian target of rapamycin) deletion improves arterial and metabolic function in old mice. 13 Together, these studies suggest that endothelial-specific inflammatory mediators can be a target for arterial dysfunction and associated metabolic dysfunction. In a series of studies in the last decade, Arf6 (ADP ribosylation factor 6) has been described as an inflammatory mediator in the vascular endothelium, although its role in arterial and metabolic function remains largely unknown.…”

“…Recent discoveries identify a host of metabolic or transcriptional regulatory genes in the endothelium that play critical roles in endothelial and metabolic dysfunction. 5,6,13 For example, endothelial-specific deletion of insulin receptor or irs2 (insulin receptor substrate 2) impairs skeletal muscle glucose uptake. 14,15 Evidence exists that EC-specific deletion of the transcription factor FoxO1 (forkhead box O1) increases skeletal muscle vascular density and suppresses obesity-associated metabolic dysfunction.…”

Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture

“…30 On the contrary, improvement in endothelium-dependent dilation in old mice lacking mammalian target of rapamycin specifically in endothelial cells was shown to ameliorate glucose and lipid tolerance and attenuate hepatic gluconeogenesis. 31 Dysfunction of sinusoidal endothelial cells in the liver has been implicated in the progression of nonalcoholic fatty liver disease via numerous mechanisms, including dysregulation of the inflammatory process, activation of hepatic stellate cells, augmentation of vascular resistance, and distortion of the microcirculation, resulting in the progression of nonalcoholic fatty liver disease. 32,33 Cardiac Influence on Systemic Metabolism…”