# New roles of endothelial regrowth in ischemic tissue recovery and regeneration

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $566,789

## Abstract

Project Summary
Tissue regeneration and repair is essential for maintaining physiological homeostasis and relies on the precise
control of molecular networks that regulate, or are regulated by, the vasculature. Endothelial cells (ECs) present
in the blood and lymphatic vessels (i.e., BECs and LECs, respectively) are crucial participants in the vascular-
dependent processes that restore damaged tissue, because they control the secretion of paracrine factors from
both the vessels themselves and nearby cells. However, the mechanisms by which ECs govern the activity of
other cellular components that participate in the recovery of injured tissues have yet to be adequately
characterized. The long-term goal of our lab is to elucidate the fundamental processes that regulate blood- and
lymphatic-vessel function and to understand how disruption of these mechanisms leads to pathological vascular
defects. We have previously shown that in mice, global homozygous knockout mutations of Foxc1 and/or Foxc2
are associated with vascular anomalies; however, the mutations also lead to embryonic or perinatal lethality, so
attempts to determine how the two Foxc genes function in adult animals have generally been inconclusive. To
overcome this limitation, we generated a line of mice carrying tamoxifen-inducible, endothelial cell (EC)-specific,
compound Foxc1;Foxc2 mutations (i.e., EC-Foxc-DKO mice), and the results from preliminary investigations
with these animals indicate that the mutations impair regeneration of the small intestine after ischemia-
reperfusion (I/R) injury by causing defects in (1) the regrowth of intestinal blood and lymphatic vessels, (2) the
formation of subepithelial stromal cells (e.g., telocytes), (3) the expression of CXCL12 and R-spondin3 in
intestinal BECs and LECs, respectively and (4) activation of the Wnt/β-catenin pathway in intestinal stem cells
(ISCs). CXCL12 is known to regulate angiogenesis, while R-spondin3 protects mice from vascular leakage, and
the two factors cooperatively stimulate canonical Wnt/β-catenin signaling, which subsequently regulates the
proliferation of ISCs. Thus, our central hypothesis is that the transcriptional activity of Foxc1/c2 in BECs and
LECs contributes to vascular repair and intestinal regeneration by regulating CXCL12 and R-spondin3 signaling.
We will test our central hypothesis by pursuing the two Specific Aims: (1) To determine whether Foxc1 and Foxc2
are required for repair of the intestinal vasculature during recovery from intestinal injury, (2) To determine the
mechanisms by which Foxc1 and Foxc2 regulate blood vessel recovery and intestinal regeneration, and (3) To
determine whether Foxc1 and Foxc2 regulate lymphatic vessel recovery and intestinal regeneration. In summary,
the experiments described in this proposal will provide crucial information about how Foxc1/c2 expression in
vascular ECs contributes to intestinal repair and regeneration. Furthermore, since vascular deficiencies
contribute to a...

## Key facts

- **NIH application ID:** 10596161
- **Project number:** 5R01HL159976-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Tsutomu Kume
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $566,789
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596161

## Citation

> US National Institutes of Health, RePORTER application 10596161, New roles of endothelial regrowth in ischemic tissue recovery and regeneration (5R01HL159976-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10596161. Licensed CC0.

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