Yang Jiao1, Guangxin Li1, Qingle Li1, Rahmat Ali1, Lingfeng Qin1, Wei Li1, Yibing Qyang1, Daniel M Greif1, Arnar Geirsson1, Jay D Humphrey1, George Tellides2. 1. From the Department of Surgery (Y.J., G.L., Q.L., R.A., L.Q., W.L., A.G., G.T.), Department of Internal Medicine (Y.Q., D.M.G.), and Vascular Biology and Therapeutics Program (Y.Q., D.M.G., A.G., J.D.H., G.T.), Yale University School of Medicine, New Haven, CT; Department of Vascular Surgery, Peking University People's Hospital, Beijing, P. R. China (Y.J., Q.L., W.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.). 2. From the Department of Surgery (Y.J., G.L., Q.L., R.A., L.Q., W.L., A.G., G.T.), Department of Internal Medicine (Y.Q., D.M.G.), and Vascular Biology and Therapeutics Program (Y.Q., D.M.G., A.G., J.D.H., G.T.), Yale University School of Medicine, New Haven, CT; Department of Vascular Surgery, Peking University People's Hospital, Beijing, P. R. China (Y.J., Q.L., W.L.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); and Veterans Affairs Connecticut Healthcare System, West Haven (G.T.). george.tellides@yale.edu.
Abstract
OBJECTIVE: Elastin deficiency because of heterozygous loss of an ELN allele in Williams syndrome causes obstructive aortopathy characterized by medial thickening and fibrosis and consequent aortic stiffening. Previous work in Eln-null mice with a severe arterial phenotype showed that inhibition of mTOR (mechanistic target of rapamycin), a key regulator of cell growth, lessened the aortic obstruction but did not prevent early postnatal death. We investigated the effects of mTOR inhibition in Eln-null mice partially rescued by human ELN that manifest a less severe arterial phenotype and survive long term. APPROACH AND RESULTS: Thoracic aortas of neonatal and juvenile mice with graded elastin deficiency exhibited increased signaling through both mTOR complex 1 and 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. Pharmacological blockade of mTOR by rapalogs did not improve luminal stenosis but reduced mechanosignaling (in delayed fashion after 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. CONCLUSIONS: 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.
OBJECTIVE:Elastindeficiency because of heterozygous loss of an ELN allele in Williams syndrome causes obstructive aortopathy characterized by medial thickening and fibrosis and consequent aortic stiffening. Previous work in Eln-null mice with a severe arterial phenotype showed that inhibition of mTOR (mechanistic target of rapamycin), a key regulator of cell growth, lessened the aortic obstruction but did not prevent early postnatal death. We investigated the effects of mTOR inhibition in Eln-null mice partially rescued by humanELN that manifest a less severe arterial phenotype and survive long term. APPROACH AND RESULTS: Thoracic aortas of neonatal and juvenile mice with graded elastindeficiency exhibited increased signaling through both mTOR complex 1 and 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. Pharmacological blockade of mTOR by rapalogs did not improve luminal stenosis but reduced mechanosignaling (in delayed fashion after 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. CONCLUSIONS: 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 elastindeficiency. Our findings suggest that mTOR-sensitive perturbation of smooth muscle cell mechanosensing contributes to elastin aortopathy.
Authors: Dos D Sarbassov; Siraj M Ali; Shomit Sengupta; Joon-Ho Sheen; Peggy P Hsu; Alex F Bagley; Andrew L Markhard; David M Sabatini Journal: Mol Cell Date: 2006-04-06 Impact factor: 17.970
Authors: Wei Li; Qingle Li; Lingfeng Qin; Rahmat Ali; Yibing Qyang; May Tassabehji; Barbara R Pober; William C Sessa; Frank J Giordano; George Tellides Journal: Arterioscler Thromb Vasc Biol Date: 2013-03-14 Impact factor: 8.311
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Austin J Cocciolone; Jie Z Hawes; Marius C Staiculescu; Elizabeth O Johnson; Monzur Murshed; Jessica E Wagenseil Journal: Am J Physiol Heart Circ Physiol Date: 2018-04-06 Impact factor: 4.733
Authors: Phoebe C R Parrish; Delong Liu; Russell H Knutsen; Charles J Billington; Robert P Mecham; Yi-Ping Fu; Beth A Kozel Journal: Hum Mol Genet Date: 2020-07-29 Impact factor: 6.150