# Reprogramming Macrophages to Improve Vascular Healing in Diabetes

> **NIH VA I01** · PROVIDENCE VA  MEDICAL CENTER · 2021 · —

## Abstract

Impaired wound healing in U.S. veterans with diabetes mellitus is a major source of morbidity and mortality as
well as a large financial strain on the VA health care system. Current treatment paradigms, including
debridement of necrotic tissue, infection control, local ulcer care, mechanical off-loading, and management of
blood glucose levels, are modestly effective at best. Despite much research in this area, the critical molecular
mechanisms regulating angiogenesis-directed wound healing remain minimally defined. Recently, our group
identified an important role for inflammatory macrophage VEGF-A production in consequent angiogenesis/
arteriogenesis required for adequate wound healing. Preliminary data support that VEGF-A expression is
increased in “classic inflammatory” macrophages relative to “alternatively activated” or wound healing
macrophages. Our preliminary data also identified that macrophage proangiogenic VEGF-A isoform expression
is dependent on expression of the potent inflammatory cytokine, IL-1β. Animals with macrophage deletion of
IL-1β demonstrated severely impaired macrophage VEGF-A expression and consequent decreases in
angiogenesis and arteriogenesis. We have begun to define a mechanistic pathway, whereby autocrine IL-1β-
IL-1R signaling promotes transcription of proangiogenic VEGF-A, in part, through activation of NF-kB and
STAT3 downstream of the IL-1R. We seek to understand the impact of diabetes on this macrophage
proangiogenic mechanism. Mice with experimental diabetes have profound delays in wound healing in a full
thickness dermal punch biopsy model and perfusion recovery in a hind limb ischemia model of femoral artery
ligation. Isolated macrophages from these diabetic mice demonstrated reduced inflammatory response to IL-1β
via reduced expression of IL-1R signaling complex components along with consequent reductions in VEGF-A
expression, consistent with the macrophage IL-1β-deletion model. The primary hypothesis is that diabetes
mellitus results in reduced macrophage IL-1β-dependent VEGF-A expression with consequent impairment in
angiogenesis-dependent wound healing, consistent with the macrophage IL-1β-deletion model. We seek to 1)
demonstrate disrupted macrophage IL-1β signaling-dependent proangiogenic VEGF-A isoform expression to
be a major mechanism of impaired angiogenesis and wound healing in DM; and 2) validate defective
monocyte/macrophage IL-1R signaling-dependent VEGF-A expression from patients with DM who develop
chronic lower extremity ulcers despite usual standard of care. By defining inflammatory macrophages as key,
early drivers of angiogenesis required for adequate wound healing, our proposed studies support a paradigm
shift away from an anti-inflammatory macrophage strategy being required to activate wound healing, allowing
for macrophage reprograming strategies that promote appropriate activation of inflammatory macrophages
toward consequent angiogenesis-dependent wound healing.

## Key facts

- **NIH application ID:** 10260749
- **Project number:** 1I01CX002231-01A1
- **Recipient organization:** PROVIDENCE VA  MEDICAL CENTER
- **Principal Investigator:** Alan Ross Morrison
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260749

## Citation

> US National Institutes of Health, RePORTER application 10260749, Reprogramming Macrophages to Improve Vascular Healing in Diabetes (1I01CX002231-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10260749. Licensed CC0.

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