# Regulation of Vascular Calcification by Adventitial Endothelial Cells

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $187,056

## Abstract

PROJECT SUMMARY/ABSTRACT
Vascular calcification affects ~60% of adults over 60 years of age and is frequently seen in patients with
atherosclerosis. Atherosclerotic calcification is an independent risk factor for cardiovascular morbidity and
mortality. Despite decades of research, no medical therapy has been convincingly established to prevent or
reverse vascular calcification. The intimal (luminal) endothelium forms the innermost layer of the vasculature.
Under disease conditions, the intimal endothelial cells (ECs) are stimulated to transform into osteoprogenitor
cells through endothelial-mesenchymal transitions and contribute to vascular calcification. ECs in the adventitia
contribute to neoangiogenesis in vascular disease. However, little is known about whether adventitial ECs are
associated with vascular calcification. During bone development, a subset of ECs defined by high expression of
the EC marker CD31 and the glycoprotein Endomucin (Emcn) are critical for bone formation. Our preliminary
study using Matrix Gla Protein (Mgp) knockout (Mgp-/-) mice as a model of vascular calcification revealed two
distinct populations of ECs in the calcified aortas, the intimal ECs (i-ECs) defined by CD31+Emcn- and the
adventitial ECs (a-ECs) characterized by CD31+Emcn+. These two EC subtypes with distinct Emcn expression
levels were also detected in human calcified arteries. Bulk RNA sequencing studies showed i-ECs were enriched
in stem cell and osteogenic markers and a-ECs exhibited upregulated Notch expression. Endothelial deletion of
the Notch1 gene reduced vascular calcification and increased the survival of the Mgp-/- mice. In this proposal,
we hypothesize that a-ECs support the biomineralization in the vascular calcification in animal models and
human atherosclerotic lesions, and are closely regulated by Notch signaling. In Aim 1, we will define the
molecular signature of the a-EC (CD31+Emcn+) population in vascular calcification using single cell RNA
sequencing. We will delineate the developmental trajectories of a-ECs in vascular calcification with correlation
to the extent and severity of calcification. In Aim 2, we will determine the contribution of endothelial subtypes (a-
ECs and i-ECs) and Notch signaling in atherosclerotic calcification. We will investigate the effect of endothelial-
specific deletion of the Notch1 receptor on EC subtypes, calcification and transcriptional profiles in
atherosclerotic lesions. The proposed studies will provide novel insight into the fundamental mechanisms of
endothelial cell biology in atherosclerotic calcification and may identify potential gene targets for selective
therapeutic modulation. Together with the mentored career development plan, the completion of the projects will
serve as a foundation to facilitate the candidate to transition into a successful and independent physician scientist
in cardiovascular research.

## Key facts

- **NIH application ID:** 10642619
- **Project number:** 1K08HL168147-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Xinjiang Cai
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $187,056
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10642619

## Citation

> US National Institutes of Health, RePORTER application 10642619, Regulation of Vascular Calcification by Adventitial Endothelial Cells (1K08HL168147-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10642619. Licensed CC0.

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