# Cardiovascular disease (CVD) and the endothelial bone marrow niche: Project 2

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $394,502

## Abstract

In contrast to other vascular territories, fairly little is known about bone marrow vasculature pathologies that
occur in individuals with atherosclerosis and acute myocardial infarction (MI). This is an important gap in our
knowledge because the bone marrow endothelium, as an integral contributor to the hematopoietic niche,
regulates the output and phenotype of disease-promoting leukocytes. These leukocytes, especially monocytes
and neutrophils, migrate to atherosclerotic lesions and ischemic myocardium to promote tissue destruction and
death. Their life span in inflamed tissue can be less than a day. Hence, myeloid cell production must be
considered a central driver of inflammation and disease. The causal relationship of systemic leukocytosis and
cardiovascular disease (CVD) progression is well documented, and clinical studies show a strong association
of leukocytosis with cardiovascular mortality. Our overarching hypothesis states that cardiovascular risk factors
and disease modulate the function of the bone marrow vasculature. Based on bone marrow endothelial cells'
role as an essential component of the hematopoietic niche, we hypothesize that acute MI and atherosclerosis
modify the crosstalk between endothelial (EC) and hematopoietic stem and progenitor cells (HSPC), giving rise
to CVD-accelerating positive feed back loops. We propose to identify the pathways that lead to altered
endothelial instruction of HSPC, resulting in accelerated monocyte and neutrophil production and increased
release of leukocytes into systemic circulation. Inhibiting these pathways will diminish the higher HSPC
proliferation rates and myeloid lineage bias, will moderate the release of newly produced leukocytes from the
bone marrow, and will ultimately counteract the increased systemic supply of CVD-promoting leukocytes. In
collaboration with our PPG colleagues, we will pursue studies investigating endothelial and vascular biology in
the marrow of mice with atherosclerosis or acute myocardial infarction. Selecting upregulated targets from
gene expression profiling in mice with CVD, we propose to investigate hematopoiesis and leukocyte levels in
EC-specific KO mice. We will then induce MI and atherosclerosis in KO mice, testing the hypothesis that they
are protected against leukocyte overproduction and cardiovascular pathology. This work will identify novel
therapeutic targets in the bone marrow endothelium. In collaboration with Dr. Lin, we will employ new
technology to image bone marrow vascular function in mice with acute MI or atherosclerosis. Specifically, we
will image blood flow to estimate shear stress, endothelial dysfunction (vascular ability to constrict and dilate),
vascular-associated collagen, angiogenesis and vascular leakage. These parameters will be integrated with
serial imaging of HSPC proliferation and leukocyte migration. The experiments will reveal how bone marrow
vascular parameters change in CVD, and how these changes contribute to systemic ov...

## Key facts

- **NIH application ID:** 9987719
- **Project number:** 5P01HL142494-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Matthias Nahrendorf
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,502
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987719

## Citation

> US National Institutes of Health, RePORTER application 9987719, Cardiovascular disease (CVD) and the endothelial bone marrow niche: Project 2 (5P01HL142494-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987719. Licensed CC0.

---

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