# Metabolic control of vascular smooth muscle cell plasticity

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $636,178

## Abstract

The dedifferentiation of vascular smooth muscle cells (SMCs) into synthetic SMCs, a hallmark of many
occlusive vascular diseases, is associated with a metabolic switch that is characterized by increased aerobic
glycolysis, which also fuels mevalonate metabolism, decreased glucose oxidation and increased fatty acid
oxidation. However, the molecular links between environmental cues and the metabolic reprogramming remain
poorly understood. Our pilot studies revealed that cyclin dependent kinase 8 (CDK8) is a master regulator of
the metabolic control of vascular SMC dedifferentiation for intimal hyperplasia toward vascular occlusion.
Mechanistic investigations uncovered that CDK8 controls the SREBP2 (sterol regulatory element binding
factor-2)-operated transcription to promote the mevalonate metabolism for protein geranylgeranylation, which
drives the vascular SMC dedifferentiation. Thus, we propose a novel paradigm in which CDK8 controls the
mevalonate metabolism for protein geranylgeranylation to promote the dedifferentiation of vascular SMCs for
intimal hyperplasia, thereby contributing to occlusive vascular disease. We will test this hypothesis and
delineate the molecular mechanisms of CDK8-operated metabolic control of vascular SMC dedifferentiation by
2 specific aims: Aim 1 will establish a mediator role of CDK8 in vascular SMC dedifferentiation into synthetic
SMCs for intimal hyperplasia toward vascular occlusion; Aim 2 will determine the underlying molecular
mechanisms with a focus on the molecular network by which CDK8 operates the mevalonate metabolism
pathway for protein geranylgeranylation which is required for vascular SMC dedifferentiation into synthetic
SMCs leading to intimal hyperplasia toward vascular occlusion. This proposal will provide the first assessment
of CDK8-mediated occlusive vascular lesion formation and define a novel pathway of occlusive vascular
remodeling that is mediated by previously unrecognized CDK8-operated metabolic reprogramming for vascular
SMC dedifferentiation, thus shedding light on the study of vascular SMC plasticity as well as the development
of innovative and effective therapeutic approaches for occlusive vascular disease.

## Key facts

- **NIH application ID:** 10334766
- **Project number:** 1R01HL160541-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Taixing Cui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $636,178
- **Award type:** 1
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334766

## Citation

> US National Institutes of Health, RePORTER application 10334766, Metabolic control of vascular smooth muscle cell plasticity (1R01HL160541-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10334766. Licensed CC0.

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