# Smooth Muscle Cell Proliferation and Degradative Phenotype in Thoracic Aorta Aneurysm and Dissection

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $773,693

## Abstract

PROJECT SUMMARY
Thoracic aortic aneurysm and dissection (TAAD) are a poorly understood group of disorders responsible for
significant morbidity and mortality in both sexes and all age groups, but without specific pharmacotherapy.
Elucidation of disease mechanisms focus on conspicuous areas of medial smooth muscle cell (SMC) loss,
whereas foci of SMC proliferation are overlooked. We found that the number of SMCs is increased in clinical
specimens of TAAD, as have several other investigators. We considered that excessive SMC proliferation may
exacerbate TAAD as dividing cells transition from a contractile phenotype to enter the cell cycle and daughter
cells may interrupt interactions with contiguous elastic laminae or drive growth of the vessel wall. To test our
hypothesis that SMC proliferation and proliferative signaling contributes to aortopathy, we developed a novel
experimental model. Conditional deletion of Tsc1, a component of the tuberous sclerosis complex, in postnatal
murine SMCs leads to activation of a key kinase, mechanistic target of rapamycin (mTOR), that regulates cell
proliferation among other processes. Our preliminary studies reveal that induction of mTOR signaling and SMC
proliferation cause progressive TAAD associated with a novel "degradative phenotype" of SMCs. Our goals are
to understand cellular and molecular mechanisms of the disease process and to determine if relevant in other
experimental models and clinical specimens of TAAD. We do not believe that the acquisition of a subset of
macrophage markers and functions by degradative SMCs in the aortic media represents transdifferentiation to
macrophages as recently described in atherosclerotic plaques. Rather, degradative SMCs acquire certain
properties that mimic macrophage maturation, including increased protease secretion, phagocytosis,
endocytosis, autophagy, and lysosome activity. Greater proteolysis, together with sequelae from loss of
contractile and synthetic activity, lead to elastic fiber fragmentation and TAAD, though clearance of extracellular
debris and recycling of macromolecules may retard disease progression. Our hypothesis is provocative and our
preliminary data compelling. Completion of our proposed experiments will yield considerable insight into the
pathogenesis of TAAD and other mTOR-dependent arteriopathies, such as atherosclerosis and aortic stiffening,
and discover new therapeutic targets for this lethal disease.

## Key facts

- **NIH application ID:** 10132382
- **Project number:** 5R01HL146723-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jay D. Humphrey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $773,693
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132382

## Citation

> US National Institutes of Health, RePORTER application 10132382, Smooth Muscle Cell Proliferation and Degradative Phenotype in Thoracic Aorta Aneurysm and Dissection (5R01HL146723-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10132382. Licensed CC0.

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