mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d6783361e236">Objective</h5> <p id="P1">Elastin deficiency due to heterozygous loss of an <i>ELN</i> allele in Williams syndrome causes obstructive aortopathy characterized by medial thickening and fibrosis and consequent aortic stiffening. Previous work in <i>Eln</i>-null mice with a severe arterial phenotype showed that inhibition of mechanistic target of rapamycin (mTOR), a key regulator of cell growth, lessened the aortic obstruction but did not prevent early postnatal death. We investigated effects of mTOR inhibition in <i>Eln</i>-null mice partially rescued by human <i>ELN</i> that manifest a less severe arterial phenotype and survive long-term. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d6783361e253">Approach and Results</h5> <p id="P2">Thoracic aortas of neonatal and juvenile mice with graded elastin deficiency exhibited increased signaling through both mTOR complex 1 and complex 2. Despite lower predicted wall stress, there was increased phosphorylation of focal adhesion kinase, suggestive of greater integrin activation, and increased transforming growth factor-β signaling mediators, associated with increased collagen expression. Pharmacologic blockade of mTOR by rapalogs did not improve luminal stenosis, but reduced mechanosignaling (in delayed fashion following mTOR complex 1 inhibition), medial collagen accumulation, and stiffening of the aorta. Rapalog administration also retarded somatic growth, however, and precipitated neonatal deaths. Complementary, less toxic strategies to inhibit mTOR via altered growth factor and nutrient responses were not effective. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d6783361e258">Conclusions</h5> <p id="P3">In addition to previously demonstrated therapeutic benefits of rapalogs decreasing smooth muscle cell proliferation in the absence of elastin, we find that rapalogs also prevent aortic fibrosis and stiffening attributable to partial elastin deficiency. Our findings suggest that mTOR-sensitive perturbation of smooth muscle cell mechanosensing contributes to elastin aortopathy. </p> </div><p id="P4"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/06154977-672d-45c4-a3d9-6b149287a2dd/PubMedCentral/image/nihms893721u1.jpg"/> </div> </p>