Chronic mTOR activation induces a degradative smooth muscle cell phenotype

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. ChittendenMichael Simons, Jay D. Humphrey, George Tellides

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish
Pages (from-to)1233-1251
Number of pages19
JournalJournal of Clinical Investigation
Volume130
Issue number3
DOIs
StatePublished - Mar 2 2020

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