# The role of YAP1 in angiogenesis during organ regeneration

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $383,073

## Abstract

Project Summary:
Angiogenesis – the formation of new blood capillaries - plays a key role in organ regeneration. Thus, in order to
regenerate adult organs, we need to understand the mechanisms of angiogenesis during organ regeneration. It
has been reported that adult human lungs have potential to grow after unilateral pneumonectomy (PNX) and
that inhibition of angiogenesis impairs post-PNX lung growth in adult mice. The overall goal of this proposal is
to characterize the mechanism of angiogenesis during organ regeneration using lung as a model and leverage
this knowledge to develop an efficient strategy for organ regeneration. Mechanosensitive transcriptional co-
activators, Yes-associated protein (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ),
stimulate angiogenesis and control organ size and regeneration. In the lung, YAP1 activation in alveolar stem
cells promotes post-PNX lung growth. However, the role of endothelial YAP1/TAZ in angiogenesis during post-
PNX lung growth remains unclear. Our preliminary data demonstrate that knockdown of YAP1 and/or TAZ
decreases the expression of angiogenic factor receptor, Tie2, in endothelial cells (ECs) and inhibits EC
sprouting. After unilateral PNX, the expression of YAP1/TAZ and Tie2 and vascular density increased in the
remaining lung lobes. Compensatory lung growth after PNX was inhibited in VE-cadherin-specific Yap1 and/or
Taz knockout (Yap1fl/fl-Cdh5CreERT2, Yap1iΔEC, Taz iΔEC, or Yap1/TaziΔEC) mice after tamoxifen-induced
Yap1/Taz deletion. When we implanted fibrin gel on the control Yap1fl/fl mouse lung, ECs were recruited from
host lungs and made vascular networks in the implanted gels, while vascular formation was attenuated in the
gel implanted on the Yap1fl/fl-Cdh5CreERT2 mouse lungs. Parenchymal stretch and increases in microvascular
perfusion and shear stress after unilateral PNX contribute to post-PNX lung growth. Insertion of silicone
prosthesis to replace an excised lobe prevented post-PNX lung growth and decreased YAP1/TAZ expression.
Ligation of right cardiac lobe pulmonary artery stimulated lung growth of the remaining non-occluded lobes
after left PNX. We hypothesize that angiogenesis is stimulated during compensatory lung growth after PNX
through mechanosensitive endothelial YAP1/TAZ signaling. In Aim 1, we will investigate the mechanism by
which endothelial YAP1/TAZ control angiogenic signaling during post-PNX lung growth in vitro. In Aim 2, we
will determine whether endothelial YAP1/TAZ control blood vessel formation during post-PNX lung growth in
the mouse lung. In Aim 3, we will investigate the effects of mechanical environment altered by PNX on blood
vessel formation in the mouse lung. Our focus on the new mechanosensitive mechanism of angiogenesis
during post-PNX lung growth and the novel mouse lung gel implantation system are highly unique and
innovative scientific advances. If this study validates that endothelial YAP1/TAZ stimulate angiogenesis in the
...

## Key facts

- **NIH application ID:** 9963345
- **Project number:** 5R01HL142578-02
- **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:** $383,073
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963345

## Citation

> US National Institutes of Health, RePORTER application 9963345, The role of YAP1 in angiogenesis during organ regeneration (5R01HL142578-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963345. Licensed CC0.

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