# Uncoupling of IL-1 beta and VEGF-A Crosstalk Contributes to Impaired Arteriogenesis Response to Ischemia in Chronic Diabetes Mellitus

> **NIH NIH P20** · OCEAN STATE RESEARCH INSTITUTE, INC. · 2021 · $186,907

## Abstract

Peripheral artery disease (PAD) caused by atherosclerosis leads to considerable morbidity and mortality 
throughout the world, in large part, due to tissue damage from both acute and chronic occlusive ischemia. 
Current treatments are limited to the modification of risk factors and mechanical revascularization by 
surgical bypass or angioplasty. Preclinical studies have identified mechanisms involving bone marrow 
derived macrophage (BMDM)-dependent angiogenesis in an inflammation suppressed state, but there is 
also a role for inflammatory macrophages during acute injury to promote effective angiogenesis. We 
recently defined a novel IL-1 B-dependent transcriptional regulation of the pro-angiogenic isoform of 
VEGF-A. Primary macrophages with deletion of IL-1 B demonstrate impaired expression of VEGF-A, and 
consequently, macrophage IL-1 beta-deleted mice have impaired angio/ arteriogenesis. Recent 
preliminary data identified that VEGF-R2 (relative to VEGFR1) expression is also elevated in the 
inflammatory M1 state and is associated with elevations in IL-1 beta and VEGF-A. Inhibition of 
VEGF-R2 signaling led to reduced VEGF-A expression despite stable IL-1 beta levels, suggesting an 
uncoupling of the relationship between IL-1 beta and VEGF-A . Additional preliminary data demonstrated 
that aged (52-week-old) mice or mice with experimental diabetes have reductions angio/ arteriogenesis, 
using a PAD model of femoral artery ligation that involves macrophage-directed blood flow recovery. 
Combined aging with chronic diabetes led to further reductions in blood flow recovery consequent to 
impaired angiogenesis. Further BMDMs from aged, diabetic mice demonstrated an uncoupling of IL-1 beta 
and VEGF-A expression, with modest reductions in IL-1 beta and yet severe and disproportionately 
reduced VEGF-A expression. VEGF-R2 was decreased in aged, diabetic BMDMs. Uncoupling of 
macrophage IL-1 beta-VEGF-A signaling contributes to impairment of inflammatory angio/arteriogenesis in 
the setting of long-term type 2 diabetes. Our study aims seek to define the mechanism whereby 
VEGF-R2 facilitates IL-1 beta-dependent VEGF-A production and consequent arteriogenesis and to 
determine the impairments in this pathway caused by aging and long-term diabetes with the goal of 
intervening to recover effective angiogenesis in the appropriate clinical context.

## Key facts

- **NIH application ID:** 10549633
- **Project number:** 5P20GM103652-09
- **Recipient organization:** OCEAN STATE RESEARCH INSTITUTE, INC.
- **Principal Investigator:** Elizabeth O Harrington
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $186,907
- **Award type:** 5
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10549633

## Citation

> US National Institutes of Health, RePORTER application 10549633, Uncoupling of IL-1 beta and VEGF-A Crosstalk Contributes to Impaired Arteriogenesis Response to Ischemia in Chronic Diabetes Mellitus (5P20GM103652-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10549633. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*