# Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain

> **NIH NIH R01** · UNIVERSITY OF NORTH DAKOTA · 2021 · $468,207

## Abstract

Adult brain angiogenesis is required for adaptation to low energy conditions e.g. hypoxia and ischemia, and for
recovery after brain injury. Decreased brain angiogenesis may cause brain ischemia, neurodegeneration, and
damage during aging while increased angiogenesis is linked to tumorigenesis including glioblastoma among
other pathologies. Thus, an understanding of the mechanisms regulating adult cerebral angiogenesis has both
basic neuroscience and clinical/translational importance to therapeutic vessel modulation for these diseases.
The present basic neuroscience project is designed to investigate a previously unrecognized mechanism for
brain angiogenesis regulation through a novel endogenous pro-angiogenic factor, adenylosuccinate (AdSucc).
Our preliminary studies have revealed that AdSucc has an important cellular signaling role in the brain rather
than functioning just as a metabolic intermediate metabolite. We demonstrated, for the first time, that AdSucc
activates angiogenesis in assays both in vitro and in vivo, and that AdSucc induces phospholipase C
dependent increase in cytoplasmic calcium, suggesting a receptor dependent action. Both of these effects
were activated under AdSucc endogenous concentrations found under low energy conditions in the brain,
which are conditions that require angiogenesis for long term compensation. Based on our preliminary data, our
central hypothesis is that AdSucc is a brain endogenous pro-angiogenic factor. Our long term objective is to
better understand metabolic regulation for brain angiogenesis, and determine if AdSucc is a valid therapeutic
target for treating conditions where aberrant angiogenesis is involved. To test our hypothesis, we have
established and characterized a novel AdSucc synthase (ADSS) conditional knockdown (KO) mouse model
that allows for spatial and temporal control of AdSucc attenuation. We have also established in our laboratory a
minimally invasive assay to quantify brain angiogenesis in a living animal in vivo using two photon microscopy.
Our central hypothesis will be tested via the following Specific Aims: 1. Determine the role of AdSucc in brain
angiogenesis under chronic hypoxia. We will use brain vascular imaging in vivo to determine angiogenesis in
wild type and ADSS conditional KO mice under normoxia and chronic hypoxia, and confirm data with
histochemical and functional assays. 2. Determine the role of AdSucc in brain angiogenesis under normoxia.
In this aim, we will determine if AdSucc induces brain angiogenesis independently of oxygen availability.
Successful completion of these aims will test a novel mechanism for regulation of brain angiogenesis.

## Key facts

- **NIH application ID:** 10297199
- **Project number:** 1R01NS119279-01A1
- **Recipient organization:** UNIVERSITY OF NORTH DAKOTA
- **Principal Investigator:** Mikhail Y Golovko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $468,207
- **Award type:** 1
- **Project period:** 2021-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297199

## Citation

> US National Institutes of Health, RePORTER application 10297199, Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain (1R01NS119279-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10297199. Licensed CC0.

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