# Switch of Osteogenesis in Vascular Calcification

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $390,000

## Abstract

SUMMARY
Therapeutic advances in vascular calcification may have far-reaching public benefits. Vascular calcification is a
frequent complication of diabetes mellitus and associated with the increase of morbidity and mortality. Although
the precise mechanism has not been determined, vascular calcification is known to be an active process
involving ectopic bone formation, in which osteogenic differentiation occurs in the cells transdifferentiated from
other lineages. Previous studies have shown that vascular endothelial cells (ECs) switch cell fate to differentiate
into osteoblastic-like cells to contribute to vascular calcification. However, it is unknown if shifting the
transcriptional landscape of EC-derived osteoblast-like cells back to endothelial differentiation ameliorates
vascular calcification. In present proposal, we take advantage of single-cell RNA sequencing (scRNA-seq) and
connectivity Map (CMap) to identify a novel approach, aiming to shift the transcriptional landscape of EC-derived
osteoblast-like cells to endothelial differentiation and investigate its effect on vascular calcification in diabetes
mellitus. In preliminary study, we use lineage tracing, scRNA-seq and CMap query to identify cyclin-dependent
kinase 1 (CDK1) inhibition to redirect EC-derived osteoblast-like cells to endothelial differentiation and
significantly improve vascular calcification. We find a specific induction of CDK1 in EC-derived osteoblast-like
cells. We show that CDK1 deletion or its inhibitor AT7519 increases E-twenty-six specific sequence variant 2
(ETV2), which is responsible for shifting the transcriptional landscape of EC-derived osteoblast-like cells to
endothelial differentiation. Furthermore, CDK1 deletion in ECs or AT7519 reduces EC-derived osteogenesis and
decreases aortic calcification in diabetic Ins2Akita/+ mice without affecting other tissues. Therefore, we hypothesize
that CDK1 inhibition induces ETV2 to redirect EC-derived osteoblast-like cells back to endothelial differentiation
in turn to ameliorate vascular calcification in diabetes mellitus. In specific Aim 1, we will elucidate the mechanism
underlying CDK1 inhibition that shifts EC-derived osteoblast-like cells toward endothelial differentiation. In
specific Aim 2, we will determine if CDK1 inhibition ameliorates vascular calcification in a diabetic mouse model.
If successful, it will build the redirection of ill-fated cells back to normalization as a new concept, and the CDK1
inhibition may emerge as a new therapeutic approach to treat calcification in acquired vascular diseases.

## Key facts

- **NIH application ID:** 10880261
- **Project number:** 5R01HL139675-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Yucheng Yao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2018-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880261

## Citation

> US National Institutes of Health, RePORTER application 10880261, Switch of Osteogenesis in Vascular Calcification (5R01HL139675-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10880261. Licensed CC0.

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