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 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 10

Degradative SMCs in human TAAD.

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Degradative SMCs in human TAAD. Ascending aortas were procured from 24 s...
Ascending aortas were procured from 24 subjects undergoing aortic surgery (Aneurysm) or from organ donors (Nondilated). (A and B) Immunofluorescence analysis for CD45 (red), SMMHC (green), LAMP2 (also known as Mac-3; white), and overlays with DAPI-labeled nuclei (blue) showing LAMP2+ leukocytes (arrows) in the intima (I) and LAMP2+ SMCs (arrows) in the media (M); inset of spleen positive control (scale bars: 100 μm). (C) Expression of SMMHC and LAMP2 (n = 12) and correlation of SMMHC to LAMP2 (n = 24). px2, pixels squared. (D) Verhoeff stain of aortic media for elastin (scale bar: 200 μm). (E) Elastin expression (n = 12) and correlation of elastin loss to LAMP2 (n = 24). (F) H&E stain of media (scale bar: 200 μm). (G) Number of medial cells per cross section (cs) (n = 12) and correlation of medial cells to LAMP2 (n = 24). (H) Correlation of media thickness and aorta diameter to LAMP2 (n = 24). Data are represented as individual values with mean ± SEM bars or linear regression lines. *P < 0.05, **P < 0.01 by t test (C, E, and G) or Spearman’s test for r correlation coefficient (C, E, G, and H).