Partial genetic disruption of mTOR complex 1 signaling does not improve vascular endothelial function in hypercholesterolemic mice (1076.6)

Abstract

Endothelial cell senescence promotes inflammation and impairs endothelium‐dependent vasodilation. While aging, hypercholesterolemia, and caloric excess are known to drive cellular senescence through activation of mTOR, it is unknown whether reduction of the mTORC1 adapter protein RapTOR can improve vasomotor function. Thus, we used hypercholesterolemic mice (Ldlr‐/‐/apoB100/100, or LA) carrying intact copies of Raptor (LA‐Raptor+/+) or were deficient in one copy of Raptor (LA‐ Raptor+/‐). Mice were fed Western Diet for 6 or 12 months, and vasomotor function in aorta was evaluated using isolated organ chamber baths. Maximum relaxation to acetylcholine (MRACH) was progressively impaired from 6 months to 12 months in LA‐Raptor+/+ mice (69±4% and 42±7%, respectively). In contrast to our hypothesis, MRACH was not significantly improved in LA‐Raptor+/‐ mice at either time point (72±3% and 50±8%, respectively). Relaxation to acetylcholine was abrogated by L‐NAME in both strains at both time points and relaxation to nitroprusside was identical between strains at each time point, suggesting that changes in endothelial function were not masked by compensatory mechanisms (e.g., endothelium‐derived hyperpolarizing factors). Furthermore, reduction of RapTOR did not elicit changes in maximal tension generated in response to Prostaglandin F2α at either time point. Collectively, despite strong previous evidence from in vitro model systems, genetic reduction of mTORC1 signaling in vivo does not appear to be sufficient to improve vasomotor function in aging hypercholesterolemic mice. Grant Funding Source: Supported by NIH/NHLBI