# Deciphering the regulatory role of matricelluar protein CCN3 in functional collateral blood flow

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $510,510

## Abstract

PROJECT SUMMARY
Peripheral artery disease (PAD) affects more than 200 million adults worldwide. Critical limb ischemia (CLI),
the most advanced form of PAD, causes significant morbidity, mortality, and health care resource utilization.
Despite our increased understanding of the pathobiology of PAD, medical treatments remain inadequate and
revascularization (surgical and non-surgical) or amputation are unfortunately the major therapeutic options.
Therefore, it is imperative to address this important unmet clinical need, potentially by the development of
novel pharmacologic therapies combined with more effective management strategies. However, current
efforts in these areas are significantly hindered due to incomplete knowledge of the fundamental mechanisms
that govern the dysregulation of vascular function, as well as the failure to generate an effective vascular
network to restore flow. Our recent observations have identified CCN3 (Nov), a specific member of the
matricellular protein family, CCN (Cyr61, Ctgf, Nov), as an important regulator of endothelial function in the
context of neovascularization. CCN3 expression was found to be strongly reduced in limb tissues from CLI
patients. In a murine hind limb ischemia (HLI) model, global CCN3 deficiency resulted in enhanced necrosis
concomitant with decreases in tissue reperfusion, hypoxia-induced factor (HIF) signaling and VEGF-A
production - key mechanisms responsible for the loss of functional collateral blood flow in PAD. Additionally,
cell-type specific deletion of CCN3 in mice and preliminary cell-based studies indicate that endothelial cell
CCN3 deficiency plays a major role in the impairment of blood flow recovery. Restrictive deletion of CCN3 in
the endothelium phenocopies the effects of the global CCN3 knockout. This strongly suggests that endothelial
CCN3 is a positive regulator of collateral blood flow recovery following HLI. At the cellular level, loss of CCN3
results in impaired endothelial migration and tube formation, pivotal processes involved in angiogenesis
requisite for blood flow recovery. Collectively, these observations led to the central hypothesis that CCN3
serves as a critical physiological regulator in driving neovascularization and the attendant tissue perfusion. In
Aim 1, we will fully characterize the role of CCN3 in the regulation of collateral blood flow. Aim 2 is designed
to elucidate the mechanisms by which CCN3 deficiency leads to compromised neovascularization and
collateral blood flow. Finally, in Aim 3, we plan to explore the therapeutic potential of CCN3 in preclinical
models of limb ischemia. The results of these studies will elucidate the role of CCN3 in controlling
endothelial function in ischemia and the mechanisms underlying its ability to promote neovascularization and
functional collateral blood flow.

## Key facts

- **NIH application ID:** 10131258
- **Project number:** 5R01HL152074-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Zhiyong Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $510,510
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131258

## Citation

> US National Institutes of Health, RePORTER application 10131258, Deciphering the regulatory role of matricelluar protein CCN3 in functional collateral blood flow (5R01HL152074-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10131258. Licensed CC0.

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