# Osteo-Angio Coupling During Bone Repair - Resubmission - 1

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $421,654

## Abstract

PROJECT SUMMARY/ABSTRACT
One of the most critical events in fracture healing is reestablishment of a functional vascular network.
Angiogenesis, the growth of new vessels from existing vessels, depends on both biological and mechanical
cues, and growing evidence links the process of rebuilding a vascular network with the program of bone
formation. Recent data show that endothelial cells (ECs) receive signaling cues from adjacent ECs as well
as from multipotent stromal cells, including osteoprogenitor cells (OPCs), which reside in the “perivascular
niche”. This close spatial relationship between OPCs and ECs suggests functional codependency via cell–
cell contact and/or paracrine signaling. Here we propose to elucidate the cellular and molecular basis of this
effect using a novel in vivo mechanobiological model of bone repair, gene knockout, and high-resolution
three-dimensional (3D) imaging modalities. CXCL12 (SDF-1) is a soluble chemokine involved in stem cell
recruitment and differentiation, is expressed in skeletal stem cells, osteoblasts, and osteocytes, and is
upregulated in response to skeletal injury and mechanical loading. Blood vessels express CXCR4 and
endothelial cells co-localize with CXCL12-expressing cells at the injury site, suggesting that CXCL12 may
play a critical role in angiogenesis during bone repair. The overall goal of this project is to elucidate the role
of CXCL12/CXCR4 signaling in osteo-angio coupling in bone. Our central hypothesis is that OPCs locally
regulate Type H vessels through CXCL12 signaling, and that the mechanical strain environment is
communicated to the local vasculature through modulation of CXCL12 expression. Our Aims are (1) To
demonstrate functional codependency between OPCs and Type H vessels during bone repair, (2) To
determine the influence of CXCL12/CXCR4 signaling on OPC-EC coupling. (3) To perform unbiased
profiling of CXCL12+ cells during bone repair with and without mechanical stimulation. Results from these
studies will advance our fundamental understanding of mechanisms regulating osteogenesis-angiogenesis
coupling during bone repair and may reveal a key signaling pathway regulating angiogenesis in bone. Our
findings would directly impact pro-angiogenic biologics and current indications for autologous stem cell
injections to treat diminished angiogenesis, delayed healing, and nonunion.

## Key facts

- **NIH application ID:** 10002183
- **Project number:** 5R01AR073864-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** ALESHA B. CASTILLO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,654
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002183

## Citation

> US National Institutes of Health, RePORTER application 10002183, Osteo-Angio Coupling During Bone Repair - Resubmission - 1 (5R01AR073864-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10002183. Licensed CC0.

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