Chronic mTOR activation induces a degradative smooth muscle cell phenotype
Guangxin Li, … , Jay D. Humphrey, George Tellides
Guangxin Li, … , Jay D. Humphrey, George Tellides
Published March 2, 2020; First published February 10, 2020
Citation Information: J Clin Invest. 2020;130(3):1233-1251. https://doi.org/10.1172/JCI131048.
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Research Article Vascular biology

Chronic mTOR activation induces a degradative smooth muscle cell phenotype

Abstract

Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/β-catenin/MITF–dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD.

Authors

Guangxin Li, Mo Wang, Alexander W. Caulk, Nicholas A. Cilfone, Sharvari Gujja, Lingfeng Qin, Pei-Yu Chen, Zehua Chen, Sameh Yousef, Yang Jiao, Changshun He, Bo Jiang, Arina Korneva, Matthew R. Bersi, Guilin Wang, Xinran Liu, Sameet Mehta, Arnar Geirsson, Jeffrey R. Gulcher, Thomas W. Chittenden, Michael Simons, Jay D. Humphrey, George Tellides

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Figure 3

mTOR activation and inhibition in Tsc1-deficient aortas.

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mTOR activation and inhibition in Tsc1-deficient aortas. Tsc1fl/fl Myh11...
Tsc1fl/fl Myh11-CreERT2 mT/mG mice were treated with tamoxifen (Tmx) or vehicle (Veh) at 1.5 weeks of age and their thoracic aortas were analyzed at various times. (A) Western blots for indicated proteins at 3 weeks with densitometry of protein bands relative to loading controls (n = 4). (B) Similar analyses at 12 weeks (n = 4). Alternatively, tamoxifen-induced mice were treated with 1% DMSO or rapamycin (RAPA) at 2 mg/kg/d i.p. from 2 to 12 weeks and their thoracic aortas were analyzed. (C) Western blots for indicated proteins at 12 weeks with densitometry of phospho-proteins relative to total proteins and contractile proteins to loading controls (n = 3). (D) In situ examination (scale bar: 2 mm) and (E) TAAD incidence. (F) H&E stains of ascending aortas (scale bar: 100 μm) and (G) number of medial cells per cross section (cs). (H) Verhoeff–Van Gieson stains of ascending aortas (scale bar: 100 μm) and (I) number of elastin breaks per cross section (n = 9–17 per group, DMSO results pooled with similar results of untreated Cre-induced mice for greater statistical power). Data are represented as individual values with mean ± SEM bars or as box-and-whisker plots with interquartile range, median, minimum, and maximum. *P < 0.05; **P < 0.01; ***P < 0.001 for Tmx vs. Veh or RAPA vs. DMSO by 2‑way ANOVA (A–C), Fisher’s exact test (E), or t test (G and I).