# The novel mechanisms of HIV associated vascular cognitive impairment

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $376,996

## Abstract

TITLE
The novel mechanisms of HIV associated vascular cognitive impairment
ABSTRACT
The World Health Organization (WHO) reported there are approximately 38 million people living with HIV (PLWH)
around the world at the end of 2019. In last two decades, the widespread deployment of combination antiretroviral
therapy (cART) has led to a substantially decline of death rate in PLWH and increase of life expectancy. However,
the aging HIV population is experiencing an increased burden of cerebrovascular disease greater than expected
in the general population and HIV associated vascular cognative impairment (HIV-VCI), even vascular dementia
(VD, a severe form of VCI) is one major type. The underlying mechanisms is still unknown.The goal of the current
proposal is to determine the role of monocyte derived extracellular Delta like-4 (Dll4) in the progression of HIV-
VCI. Dll4 is a Notch ligand and is usually restricted in endothelial cells (ECs) of small vessels in adult human and
mouse brain. The ectopic expression of Dll4 in monocyte provides the link between systemic inflammation and
brain vessel remodeling leading to HIV-VCI. In vitro, we demonstrated that LPS induced a robust increase of
Dll4 mRNA and protein expression in human monocytes and Dll4 secretion from monocytes (extracellular Dll4,
exDll4). In vivo, mice injected with exDll4 show cerebrovascular remodeling. In clinical specimen, we found that
HIV patients on cART show a remarkable elevated plasma exDll4. The plasma exDll4 was positively associated
with intermediate subpopulation of monocytes (pro-inflammatory monocytes), indicating a strong correlation of
circulating exDll4 with inflammation. Importantly, circulating exDll4 was significantly associated with brain vessel
diameter in HIV+ patients. In inflammatory mouse model induced by LPS, we observe remarkable enhanced
Dll4 expression in monocytes and brain vascular remodeling.To explore the mechanisms of exDll4, we treated
the human endothelial cells (ECs), and human smooth muscle cells (SMCs) with exDll4. Our vitro studies showed
that exDll4 significantly inhibited Notch1 activation in ECs and repressed both Notch2 and Notch3 activation in
SMCs. Decreased Notch1 activation in ECs leads to increase of EC permeability. Therefore, we hypothesize
that monocyte derived Dll4 promotes the progression of VCI by impairing the blood brain barrier (BBB) and
increasing brain small vessel remodeling through inhibiting Notch signaling in ECs and mural cells ( include
pericytes and SMCs). To test our hypothesis, we propose the two Specific Aims:Aim 1. Define the role of exDll4
on brain vascular remodeling, cognative functions and related mechanisms in mice. Aim 2. Determine the role
of monocyte derived Dll4 on brain vascular remodeling, cognitive funtion and mechanisms in LPS induced VCI
mouse model using monocyte Dll4 (mDll4) KO mice. Accomplishing these aims will fill the knowledge gap
regarding the mechanisms of the pathogenesis of VCI.
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## Key facts

- **NIH application ID:** 10498559
- **Project number:** 3R01HL122777-08S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Jinjiang Pang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $376,996
- **Award type:** 3
- **Project period:** 2014-04-04 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498559

## Citation

> US National Institutes of Health, RePORTER application 10498559, The novel mechanisms of HIV associated vascular cognitive impairment (3R01HL122777-08S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10498559. Licensed CC0.

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