# TGFB-Dependent Mechanoresponses by Aortic Smooth Muscle Cells Govern Aneurysms

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $419,653

## Abstract

PROJECT SUMMARY
Thoracic aortic aneurysms (TAAs) affect young and old males and females and are responsible for significant
morbidity and mortality. Findings over recent years suggest that an aberrant activity of or signaling through
transforming growth factor-beta (TGFβ) plays important roles in TAAs, yet controversy remains regarding the
precise mechanisms. This lack of understanding continues to hinder the identification of improved therapeutic
approaches as revealed by the recent failure of a highly anticipated clinical trial of losartan, an angiotensin-II
receptor antagonist. We and others recently hypothesized that the collection of predisposing genetic mutations
suggests that TAAs result, in part, from a compromised cellular mechanosensing and mechanoregulation of
the extracellular matrix that endows the aortic wall with its structural integrity. Importantly, TGFβ can be
viewed, in part, as a critical mechanotransducer – its production and activation are mechanosensitive
and its downstream gene products include the contractile proteins that are fundamental to sensing
and regulating the extracellular matrix that is produced in response to its increased signaling.
The goal of this project is to test novel hypotheses on interactions among the structural and instructional roles
of altered TGFβ signaling, smooth muscle cell mechanosensing of altered wall stresses (particularly those due
to hypertension, a primary risk factor for TAAs), and the integrity of fibrillin-1, an essential glycoprotein that
associates with elastin to form elastic fibers. Towards this end, we will use a combination of new genetically
modified mouse models, in vivo models of induced hypertension, and clinical specimens of TAAs. We will
characterize responses of smooth muscle cells in the thoracic aorta to increased wall stresses (computed by
Core C) and disrupted fibrillin-1 that depend on TGFβ signaling and lead to maladaptive remodeling of the
aortic wall. Finally, this project will complement naturally the other 3 projects in this PPG. The results of our
work (Project 4) will extend the characterization of how graded losses of extracellular matrix integrity influence
the biological responses, including angiotensin receptor signaling, of TAAs to physiological hemodynamic
loads (Project 1), will complement investigations of biomechanical mechanisms that control the activation of
TGFβ in TAAs (Project 2), and will inform studies of endothelial flow-regulated responses and extracellular
matrix remodeling in TAAs (Project 3). As in the other three projects, we will use Core B to elucidate complex
systems-level interactions among the mechanical, structural, and biological factors studied. Coordinated via
Core A, the findings of this highly integrated PPG will contribute significantly to understanding coupled
dysfunctional mechanosensing by aortic cells and identifying new molecular targets to treat TAAs.

## Key facts

- **NIH application ID:** 10136701
- **Project number:** 5P01HL134605-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Jay D. Humphrey
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,653
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136701

## Citation

> US National Institutes of Health, RePORTER application 10136701, TGFB-Dependent Mechanoresponses by Aortic Smooth Muscle Cells Govern Aneurysms (5P01HL134605-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136701. Licensed CC0.

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