# Role of endothelial Twist1 in vascular remodeling in pulmonary hypertension

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $307,083

## Abstract

Project Summary
Pulmonary hypertension (PH) is a multifactorial life threatening pulmonary vascular disease characterized by
aberrant muscularization of the normally non-muscularized distal pulmonary arterioles (PAs). Dysfunction of
PA endothelial cells (ECs) plays key roles in accumulation of pulmonary artery smooth muscle cells (PASMCs)
to distal PAs. Expression of the transcription factor Twist1 is upregulated in the lungs of PH patients. However,
the role of endothelial Twist1 in pathogenesis of PH has not been fully understood. The goal of this proposal is
to explore the mechanism by which endothelial Twist1 controls accumulation of PASMCs to distal PAs. Our
new preliminary data demonstrate that Twist1 overexpression increases the levels of platelet-derived growth
factor B (PDGFB) in human pulmonary arterial endothelial (HPAE) cells and induces proliferation and migration
of PASMCs. Hypoxia increases Twist1 Ser42 phosphorylation and PDGFB expression in HPAE cells and
conditioned medium from these cells stimulates migration of PASMCs, while Twist1 knockdown in ECs inhibits
the effects. When we implanted fibrin gel supplemented with fluorescently labeled ECs on the mouse lung,
Twist1 overexpression in these ECs increases PDGFB expression and promotes the recruitment of α-smooth
muscle actin (SMA)-positive cells in the gel. Hypoxia induces accumulation of αSMA-positive cells to blood
vessels formed in the gel, while Twist1 knockdown in ECs attenuates the effects. Hypoxia also stimulates
accumulation of αSMA-positive cells to small PAs in the mouse lungs, which is suppressed in Tie2-specific
Twist1 knockout mice. The levels of Twist1 and PDGFB are higher in lung ECs isolated from mice with type-2
bone morphogenetic protein receptor (Bmpr2) mutation that influences the severity of human PH. The Bmpr2
mutation also stimulates accumulation of αSMA-positive cells to ECs in the gel implanted on the hypoxia-
treated mouse lungs. We hypothesize that endothelial Twist1 mediates hypoxia-induced SMC accumulation to
distal PAs through PDGFB paracrine signaling. In Aim 1, we will investigate whether endothelial Twist1 or its
phosphorylation controls PASMC behaviors through PDGFB paracrine signaling in vitro. In Aim 2, we will
determine whether endothelial Twist1 mediates hypoxia-induced SMC accumulation to blood vessels in the
mouse lung using the mouse lung fibrin gel implantation system. We will also explore whether endothelial
Twist1 mediates hypoxia-induced vascular remodeling using inducible VE-cadherin-specific Twist1 knockout
mice. In Aim 3, we will investigate whether endothelial Twist1 mediates Bmpr2 mutations-induced vascular
remodeling in ECs under normoxia or hypoxia in vitro and in the gel implantation model. Our focus on exploring
the role of endothelial Twist1 in hypoxia-induced SMC accumulation to distal PAs using the mouse lung gel
implantation system is unique and relevant advances, which will further our understanding of the pathogenesis
...

## Key facts

- **NIH application ID:** 9852580
- **Project number:** 5R01HL139638-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** TADANORI MAMMOTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,083
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852580

## Citation

> US National Institutes of Health, RePORTER application 9852580, Role of endothelial Twist1 in vascular remodeling in pulmonary hypertension (5R01HL139638-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852580. Licensed CC0.

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