# Role of Monocyte Delta Like-4 (Dll4) in HIV-Associated Cerebral Small Vessel Disease

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $757,725

## Abstract

The goal of the current proposal is to determine the role of monocyte Delta like-4 (Dll4) in cerebral small vessel
disease (CSVD) and its impact on cognition in people with HIV (PWH). Dll4 is a Notch ligand usually restricted
in endothelial cells (ECs). However, monocytes can express DII4 under pro-inflammatory conditions. This is
relevant to the current era of combination antiretroviral therapy (cART), where persistent systemic inflammation
is a driving force for the progression of comorbidities.
 Our preliminary data strongly suggest that DII4-Notch signaling is implicated in altering cerebrovascular
function. In vitro, we demonstrate that pro-inflammatory stimuli such as lipopolysaccharides (LPS) or tumor
necrosis factor alpha (TNFα) (often increased in HIV infection) induce a robust increase of Dll4 expression in
human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Monocytes with high Dll4
expression trigger Notch1 activation to promote a pro-inflammatory status. In vivo, mice injected with exDll4
show impaired blood-brain barrier (BBB) and cerebrovascular remodeling. Of interest, exDll4 inhibits Notch1
activation in human brain microvascular endothelial cells (HBMECs) and Notch2/ 3 activation in human brain
vascular smooth muscle cells (HBVSMCs).
 In clinical specimens, we have found sex differences in exDII4 plasma levels of PWH on cART, elevated in
males but not in females compared to HIV uninfected study participants. However, membrane-bound DII4 levels
were similar in males and females, suggesting novel pathways that may contribute to the previously reported
sex differences in cerebrovascular disease. Based on the observations above, we hypothesize that monocyte
DII4-Notch signaling contributes to a monocyte pro-inflammatory phenotype in both male and female PWH. Pro-
inflammatory monocytes are more likely to interact with endothelial cells (ECs) and cross the BBB differentiating
in perivascular macrophages, thus contributing to neuroinflammation and CSVD. In addition, male PWH have
increased levels of exDII4 in circulation, which could further affect the BBB through inhibition of Notch1 signaling
in ECs and Notch3 signaling in pericytes. exDII4 also increases vascular remodeling in small arteries and
arterioles, leading to ischemia as reflected by lacunae and white matter hyperintensities, typical manifestations
of CSVD. We will test these hypotheses by addressing the three aims listed below:
 Aim 1. To determine, in a longitudinal study, the role of monocytes derived DII4 in brain microcirculation
and microstructure integrity.
 Aim 2. To determine, in an integrated approach, the effects of HIV status, imaging metrics, exDII4, and
mDII4 levels on cognitive performance.
 Aim 3. To define the role of mDll4 on molecular mechanisms of monocyte transmigration and the
mechanistic role of exDll4 on vascular cell function.

## Key facts

- **NIH application ID:** 10837487
- **Project number:** 1R01NS132870-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Jinjiang Pang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $757,725
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837487

## Citation

> US National Institutes of Health, RePORTER application 10837487, Role of Monocyte Delta Like-4 (Dll4) in HIV-Associated Cerebral Small Vessel Disease (1R01NS132870-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10837487. Licensed CC0.

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