# Define the mechanisms of aortopathy in bicuspid aortic valve patients

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $696,752

## Abstract

Thoracic aortic aneurysm occurs in approximately 50–70% of patients with bicuspid aortic valve (BAV), which
affects 1–2% of the general population. There is a critical need to develop evidence to determine criteria for
surgical intervention and to develop treatment that will prevent or reverse aneurysms for BAV patients. Thoracic
aortic aneurysm in BAV frequently involves the proximal aorta, with smooth muscle cells (SMCs) that originate
from neural crest stem cells (NCSCs). However, it spares the descending thoracic aorta, which has SMCs that
originate from the paraxial mesoderm. The long-term goal of our research is to determine the molecular
mechanisms responsible for the aortopathy associated with BAV and develop therapeutic strategies for aortic
aneurysm in BAV. The objective of this research is to model BAV aortopathy in vitro using SMCs derived from
BAV induced pluripotent stem cells (iPSCs) and in vivo using tissue-engineered vessels generated from these
SMCs. Models will be used to explore treatments for aortic aneurysm in BAV. Our central hypothesis is that BAV
aortic SMCs are defective in TGF--dependent differentiation of SMCs from NCSCs but not paraxial mesoderm
and this defect causes decreased contractile function and secretion of extracellular matrix from these cells,
resulting in aortopathy and subsequent aneurysm at the proximal aorta in BAV. Aim 1: We will characterize
defects in vascular SMC differentiation in BAV/aneurysm cases in vitro. We will differentiate BAV and control
iPSCs into NCSCs and paraxial mesoderm, then SMCs. We will determine the differentiation, contractility, and
extracellular matrix of the BAV- and control-SMCs. We will define the key signaling pathway leading to defective
differentiation in BAV NCSC-SMCs with a focus on canonical TGF-β signaling and myocardin transcription as
identified in our pilot study. We will also perform RNA-seq to unbiasedly identify other potential pathways causing
the defective differentiation of SMCs from NCSCs. We will rescue the defective differentiation of BAV SMCs from
the NCSC lineage through pathways independent of the TGF- pathway, such as rapamycin, which promotes
SMC differentiation by inhibiting mammalian target of rapamycin and activating Akt2. Aim 2: We will determine
the mechanism of aneurysm formation in vivo using nude rabbits that host engineered aorta generated from BAV
patients’ iPSCs. We will create tissue-engineered vessels populated with BAV NCSC-SMCs to replace the
rabbits’ abdominal aorta. We will determine the biomechanics and aneurysm formation of the engineered vessels
in rabbits, and we will define differentiation and maturation of the SMCs and the TGF- signaling of the
engineered vessel. Finally, we will incorporate rapamycin into the scaffold to prevent the aneurysm in engineered
vessels. Our human iPSC in vitro and in vivo model is innovative for studying the mechanisms of thoracic aortic
aneurysm in BAV and for screening therapeutic agents. These ...

## Key facts

- **NIH application ID:** 10132379
- **Project number:** 5R01HL141891-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Bo Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $696,752
- **Award type:** 5
- **Project period:** 2018-04-13 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132379

## Citation

> US National Institutes of Health, RePORTER application 10132379, Define the mechanisms of aortopathy in bicuspid aortic valve patients (5R01HL141891-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132379. Licensed CC0.

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