# Role of lactate dehydrogenase A in endothelial metabolism and angiogenesis

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2022 · $349,600

## Abstract

The blood vascular system is an extensive network that provides tissues with oxygen, nutrients, and a variety of 
angiocrine factors. It is formed mainly through angiogenesis, a process in which new blood vessels grow from 
the existing vasculature. Angiogenesis is vital for embryonic development, tissue growth, and regeneration, and 
is also involved in the pathogenesis of many human diseases. For example, proliferative diabetic retinopathy 
(PDR) and retinopathy of prematurity (ROP) are eye disorders that may lead to vision loss in diabetic patients 
and premature babies respectively. Both of these ocular diseases are characterized by excessive retinal 
angiogenesis, which causes intravitreal hemorrhage, macular edema, and even retinal detachment. However, 
current treatment strategies to inhibit aberrant blood vessel formation in PDR and ROP only have limited efficacy 
and may elicit undesirable side effects. Therefore, understanding the mechanisms that drive blood vessel 
formation is important because it may facilitate the development of better therapies for treating these severe eye 
diseases. Formation of new blood vessels through angiogenesis involves proliferation, migration, and several 
other energy-consuming endothelial cell (EC) behaviors. Recent studies have shown that proliferating ECs 
preferentially convert glucose to lactate and generate ~85% of ATP through glycolysis rather than glucose 
oxidation via the TCA cycle, even when the ECs are grown in an oxygen-rich environment. This metabolic feature 
is also seen in cancer cells and is termed the Warburg effect. However, it remains unclear at the molecular level 
why lactate instead of metabolites in the TCA cycle are favorably produced from glucose in proliferating ECs. 
Pilot studies from the applicant’s lab suggest that lactate dehydrogenase A (LDHA), an enzyme catalyzing the 
conversion of pyruvate to lactate and the regeneration of NAD+ from NADH, is a potentially key driver of the 
Warburg effect in ECs. The central hypothesis of this application is that LDHA controls the metabolic fate of 
glucose and sustains angiogenesis by regulating glycolytic flux in ECs. We will test this hypothesis through two 
Specific Aims. Aim 1 will use various metabolic assays and endothelial-specific Ldha knockout mice to determine 
the roles of LDHA in regulating the Warburg effect and developmental and pathological angiogenesis in the 
retina. By combining mouse genetic models, molecular and biochemical approaches, and advanced analytical 
tools, Aim 2 will identify the upstream regulator that controls LDHA expression in ECs and will elucidate the 
mechanism by which LDHA regulates endothelial growth. Collectively, our proposal will advance the 
understanding of the link between endothelial metabolism and blood vessel formation, and it will provide concrete 
steps towards developing new strategies for inhibiting angiogenesis in human ocular diseases.

## Key facts

- **NIH application ID:** 10339350
- **Project number:** 5P20GM139763-02
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** PENGCHUN YU
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,600
- **Award type:** 5
- **Project period:** 2021-02-05 → 2022-09-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339350

## Citation

> US National Institutes of Health, RePORTER application 10339350, Role of lactate dehydrogenase A in endothelial metabolism and angiogenesis (5P20GM139763-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10339350. Licensed CC0.

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