# PFKFB3 in vascular remodeling

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $570,088

## Abstract

PROJECT SUMMARY
6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase isoform 3 (PFKFB3) is a critical glycolytic
regulator in vascular cells. PFKFB3 catalyzes the synthesis of fructose-2, 6-bisphosphate (F2, 6P2) and
the latter is the most potent activator for 6-phosphofructo-1-kinase (PFK-1), one of three rate-limiting
enzymes for glycolysis. Proliferation of vascular cells including endothelial cells and vascular smooth
muscle cells is the major feature of vascular remodeling in a variety of vascular diseases including
pulmonary arterial hypertension (PAH). Ours and the work from others have demonstrated a critical role
of endothelial PFKFB3 in angiogenesis. In our recent studies we have found the following: (1)
PDGF/VEGF and hypoxia increase the protein level and activity of PFKFB3 in pulmonary artery smooth
muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs); (2) inhibition of PFKFB3
attenuates PDGF/VEGF- and hypoxia-induced collagen synthesis, hyperproliferation and resistance to
apoptosis of PASMCs and PAECs; (3) hypoxia-induced pulmonary vascular remodeling was significantly
suppressed in PFKFB3-/+ mice; (4) PFKFB3 protein levels are robustly increased in the smooth muscle
cells and endothelial cells as well as plexiform lesions of pulmonary arteries of patients with idiopathic
PAH. These data led us to hypothesize that PFKFB3 in vascular cells has a central role in vascular
remodeling and suppression of PFKFB3 inhibits proliferation of vascular cells and further curbs the
development of pulmonary arterial hypertension. The goal of this proposal is designed to use specific
PFKFB3 inhibitor and tissue-specific PFKFB3 deletion mice to investigate whether and how PFKFB3 in
vascular cells plays a crucial role in vascular remodeling of PAH. In Aim 1, we will investigate whether
PDGF/VEGF and hypoxia increase PFKFB3 activity via HIF1α-mediated PFKFB3 gene expression and
MAPK-mediated PFKFB3 phosphorylation in PASMCs and PAECs. In Aim 2, we will study whether and
how lactate, arising from high PFKFB3 activity, elevates Akt activation, leading to collagen synthesis,
hyperproliferation and resistance to apoptosis of PASMCs and PAECs. In Aim 3, we will examine whether
pulmonary vascular remodeling is suppressed in mice with PFKFB3 deficiency in smooth muscle cells or
endothelial cells, and in rat treated with a specific PFKFB3 inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-
propen-1-one (3PO). This proposal is highly translational. Completion of this project will advance a new
PFKFB3-based paradigm for the suppression of vascular remodeling and may lead to a more effective
and specific therapy of diseases associated with vascular remodeling.

## Key facts

- **NIH application ID:** 9937771
- **Project number:** 5R01HL134934-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** YUQING HUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $570,088
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937771

## Citation

> US National Institutes of Health, RePORTER application 9937771, PFKFB3 in vascular remodeling (5R01HL134934-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9937771. Licensed CC0.

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