Background: Systemic inhibition of mammalian target of rapamycin (mTOR) improves age-related arterial and metabolic dysfunction. Although the mechanisms and tissues involved in this amelioration remain unknown, endothelial cells (ECs), key regulators of arterial and metabolic function, may be responsible for these effects.

Hypothesis: The beneficial effects of systemic mTOR inhibition will be recapitulated after EC specific mTOR deletion in old mice.

Methods: We studied 22-24 mo old wildtype (WT) and EC specific tamoxifen-inducible mTOR knockout (KO) mice. The arterial function was determined by assessing aortic stiffness by measuring pulse wave velocity (PWV) using Doppler ultrasound as well as endothelium-dependent dilation (EDD) and nitric oxide (NO) bioavailability using pressure myography. Carotid artery superoxide production was measured using electric paramagnetic resonance. Glucose (2g/kg, ip) and lipid (3mL/kg, oral) tolerance tests were performed to examine metabolic function.

Results: Two weeks after tamoxifen administration (4mg/day, 4 days, oral), we found a ~ 60% reduction in EC mTOR protein (p=0.04). Aortic PWV was lower in KO compared to WT mice (Fig A), indicating lower aortic stiffness. EDD to acetylcholine (ACh) was higher in mesenteric arteries from KO compared to WT mice (Fig B) due to an increase in NO bioavailability (31.6 ± 8.6 vs 8.4 ± 2.3; p=0.01). Superoxide scavenger, TEMPOL, increased EDD in both WT and KO mice (Fig C), eliminating differences between groups. Superoxide was lower in carotid arteries of KO compared to WT (Fig D), suggesting that oxidative stress impairs EDD in WT mice and ablation of EC selective mTOR ameliorates this effect. Aged KO mice demonstrated greater glucose and lipid tolerance compared to WT (Fig E, F).

Conclusions: Our findings demonstrate that EC specific deletion of mTOR provides beneficial effects on arterial function via reductions in oxidative stress and prevents metabolic dysfunction in old mice.