# Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $394,375

## Abstract

Vascular insufficiency underlies the pathogenesis of vascular cognitive impairment and dementia
(VCID). The pathological events in VCID involves crosstalk between the CNS and peripheral
metabolic regulation, yet the details in bridging two compartments are underexplored. To fill this
gap, the present proposal focuses on the impact of the adiponectin in the progression of VCID.
Adiponectin is an adipokine mainly produced by adipocytes and secreted into the bloodstream,
regulating glucose metabolism and fatty acid oxidation. Using a mouse model of chronic cerebral
hypoperfusion-induced VCID by asymmetric common carotid artery stenosis (ACAS), we found
that adiponectin levels increased in plasma 3d to 42d after ACAS, yet were suppressed in
cerebrospinal fluid at 42d after ACAS. We obtained further promising data showing that 1)
Adiponectin knockout (KO) mice exhibited more prominent cognitive deficits up to 42d after ACAS,
whereas administration of adipoRon, a small-molecule agonist of adiponectin receptor (adipoR),
rescued long-term cognitive functions in adiponectin KO mice and attenuated cognitive deficits in
wild-type mice; 2) Adiponectin KO exacerbated, while adipoRon treatment improved long-term
white matter structural and functional integrity; 3) Adiponectin receptors AdipoR1/R2 were highly
expressed on endothelial cells (ECs); 4) Adiponectin KO exacerbated the reduction in cortical
cerebral blood flow (CBF) after ACAS; 5) AdipoRon promotes endothelial nitric oxide synthase
activation in cultured EC; 6) AdipoRon reduced blood brain barrier (BBB) leakage in vivo after
ACAS and protected from oxygen-glucose deprivation (OGD)-induced hyperpermeability in an in
vitro BBB model. 7) AdipoRon treatment inhibited neuroinflammation after ACAS and inhibited
the release of inflammatory factors from primary EC upon OGD. The current proposal will further
explore the effects of adiponectin on endothelial function in ACAS, including vasoactivity, BBB
integrity, and EC inflammation and will develop in vivo adipoRon regimen as a novel strategy to
preserve white matter and improve cognitive function. The central hypothesis is that adiponectin
ameliorates cognitive deficits and white matter injury in chronic cerebral hypoperfusion-
induced VCID at least in part by enhancing endothelial-dependent vasoactivity and BBB
integrity. Aim 1. Test if adiponectin improves endothelial-dependent vasoactivity and CBF by
enhancing vascular production of nitric oxide following chronic cerebral hypoperfusion-induced
VCID. Aim 2. Test if adiponectin inhibits endothelial inflammation and protects the BBB integrity
against hypoperfusion-induced injury. Aim 3. Test if adipoRon treatment maintains white matter
integrity and long-term neurological functions after ACAS in young and aged mice of both sexes.

## Key facts

- **NIH application ID:** 10338744
- **Project number:** 1R01NS124673-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Tuo Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $394,375
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10338744

## Citation

> US National Institutes of Health, RePORTER application 10338744, Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID) (1R01NS124673-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10338744. Licensed CC0.

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