# Cerebral arteriole structure/function in diabetic ischemic brain injury

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2020 · —

## Abstract

Acute stroke is the leading cause of adult disability. Diabetes, which affects 30% of the 800,000 annual stroke
victims, is a rapidly rising threat, increasing occurrence AND poor recovery of stroke. Recent evidence for
neural repair and recovery after stroke strongly suggests that enhancement of brain's endogenous repair
potential may improve recovery and reduce the burden of disability. However, most prior attempts focusing on
solely neural mechanisms of recovery not only limited our understanding of how the brain orchestrates
restorative and regenerative processes within the different cellular networks but also stalled the development
of new therapeutic strategies. The limited use of animal models of diabetes in preclinical stroke research has
further deepened this gap. The specific objective of this competing renewal proposal is to address this gap
by focusing on the vascular mechanisms that hinder brain plasticity and repair in diabetes. Our central
hypothesis is that “diabetes-mediated dysregulation of the neurotrophic/proangiogenic microenvironment
amplifies endothelial regulated cell death (RCD) after stroke leading to impaired vasoneuronal restoration and
functional recovery”. Our novel findings in the past funding period showed that 1) in contrast to reparative
angiogenesis in control animals, there is cerebrovascular regression associated with poor recovery of motor
and memory function after stroke in diabetes, and 2) vasoregression is associated with greater peroxynitrite
(PN) generation and cell death. Our preliminary data suggest that 1) in addition to apoptosis, necroptosis and
ferroptosis, newly described forms of RCD are activated in endothelial cells from diabetic animals after stroke,
2) these pathways are differentially activated in brain microvascular endothelial cells (BMVECs) from male and
female animals, 3) nitration of p85 subunit of PI3K by PN leads to decreased phospho(p)Akt and endothelial
cell survival, 4) mature brain derived neurotrophic factor (mBDNF) is decreased while proapoptotic proBDNF
and its cognate receptor p75NTR are increased in the diabetic brain, and 5) MMP9, a key protease involved in
matrix degradation and cleavage of BDNF receptor TrkB, is activated by nitration after stroke. Aim 1 will test
the hypothesis that multiple RCD pathways orchestrate vasoregression and poor recovery after stroke in
diabetes. Aim 2 will test the hypothesis that PN-dependent nitration inhibits prosurvival signals amplifying
endothelial RCD after diabetic stroke. The outcomes of these studies will significantly impact stroke research,
human health and VA mission because it will a) advance the existing concept of neurorestoration and
demonstrate that vascular restoration is fundamental for neuronal repair and functional recovery after stroke, b)
generate important data related to mechanisms of how endothelial and neural repair processes are attenuated
after stroke in diabetes which occurs in more than ~10% of the US population...

## Key facts

- **NIH application ID:** 9859296
- **Project number:** 5I01BX000347-12
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** ADVIYE ERGUL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859296

## Citation

> US National Institutes of Health, RePORTER application 9859296, Cerebral arteriole structure/function in diabetic ischemic brain injury (5I01BX000347-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859296. Licensed CC0.

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