# Sexual dimorphism in antigen-independent angiogenesis inhibition of IgG1 antibodies

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2022 · $35,615

## Abstract

PROJECT SUMMARY
Many diseases of excess, abnormal, or insufficient angiogenesis such as peripheral artery disease, neovascular
age-related macular degeneration, solid tumors, peripheral artery disease, and heart failure exhibit sexual
dimorphism with respect to risk factors, incidence, and optimal interventions. Despite widespread
acknowledgement of these disparities, the molecular mechanisms that promote sex differences in vascular
conditions are understudied. Studies from our lab established that human IgG1 (and the murine equivalents
IgG2a/c) possess intrinsic anti-angiogenic activity which occurs independently of antigen binding. Instead, this
activity is due to recognition of the Fc domain of IgG1 by the high-affinity activating receptor FcγRI in
macrophages. We term this activity “antibody-dependent cell-mediated angioinhibition” (ADCAI). These findings
suggest that ADCAI is an evolutionarily conserved, fundamental process that affects vascular remodeling in
multiple tissue beds and physiologic states. Prompted by the NIH's Guidelines on Sex as a Biological Variable,
we recently made several striking observations suggesting that female animals and female-derived cells exhibit
markedly reduced ADCAI compared to males. These findings raise the intriguing possibility that sex disparities
in vascular remodeling may arise from differences in ADCAI responses. However, the mechanisms responsible
for ADCAI sex differences, and whether ADCAI disparities are conserved in humans are unknown. Here, I
propose to further investigate the mechanisms underlying sexual dimorphism in ADCAI. Specifically, I will
determine the role of the gene DDX3Y, which was identified as a potential mediator of ADCAI in an unbiased
screen of Y chromosome encoded genes (Aim 1). I will also investigate the affects that gonadectomies have on
ADCAI (Aim 2). In addition, I will test whether ADCAI sex differences are conserved in human macrophages and
humanized Fc receptor mice (Aim 3). My central hypothesis is that sexual dimorphism of ADCAI is a conserved
process that is potentiated by expression of DDX3Y in macrophages. This project will shed new light on the
contrasts between the angiogenesis regulation between sexes, revealing new pathways and targets to modulate
angiogenesis in a more personalized manner to improve therapeutic outcomes.

## Key facts

- **NIH application ID:** 10536062
- **Project number:** 1F31HL160109-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Dionne Alexis Argyle
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $35,615
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536062

## Citation

> US National Institutes of Health, RePORTER application 10536062, Sexual dimorphism in antigen-independent angiogenesis inhibition of IgG1 antibodies (1F31HL160109-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536062. Licensed CC0.

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