# Insights into the molecular mechanisms regulating vascular and immune metabolism in vascular diseases

> **NIH NIH R35** · YALE UNIVERSITY · 2022 · $948,192

## Abstract

PROJECT SUMMARY
Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic disease characterized by lipid
retention and vascular inflammation. Endothelial cells (ECs), smooth muscle cells (SMCs) and macrophages
are recognized to have a unique impact on the disease progression. It is recently recognized that specific
dysregulation of metabolic signaling pathways contributes to certain aspects of EC, macrophage and SMC
homeostasis. For instance, during the process of atherosclerosis, ECs are exposed to a pro-inflammatory
milieu that enhances glycolysis and reduces fatty acid oxidation in ECs and predisposes them to undergo
mesenchymal transition (EndMT), which may affect plaque stability. The implications of non-coding RNAs,
including microRNAs (miRNAs), in cardiovascular disease is well recognized, representing the most rapidly
evolving research field. Furthermore, miRNAs have emerged as critical regulators of cellular metabolism (e.g.
miR-33) and therefore can directly regulate EC metabolic responses that can determine the progression of
atherosclerosis, although this aspect has not been elucidated yet. Moreover, miRNAs can promote the
acquisition of mesenchymal markers (e.g. miR-21) that can in turn shape their metabolic response and
mesenchymal phenotype, thus affecting EC atherosclerotic phenotype. This has also not been investigated
in detail. In this regard, similar mechanisms may be involved in the phenotypic regulation of SMC during
atherosclerosis, and need to be explored as well. A vast literature has demonstrated that miRNAs play
important roles in macrophage functions by regulating macrophage inflammatory responses and
lipid metabolism. Increasing evidence indicates that a substantial crosstalk exists between innate immune
signaling and metabolic pathways. Macrophage activation and differentiation prominently feature the
modulation of genes involved in general cellular metabolic activities. In this regard, downregulation of
cholesterol biosynthetic genes in classically activated macrophages is linked to regulation of inflammatory
reactions elicited by macrophages. A critical outstanding question is how the dynamic interplay between
cholesterol, cholesterol biosynthetic intermediates and cholesterol derivatives influences macrophage foam
cell formation and inflammation, which are key determinants of atherosclerosis progression. On the whole,
this research program aims to elucidate different mechanisms that regulate cell-specific metabolic signaling
pathways and how they are involved in the progression of atherosclerosis. Targeting cell-specific metabolic
processes could become another potential therapeutic targeting strategy for treating metabolic disorders.

## Key facts

- **NIH application ID:** 10329985
- **Project number:** 5R35HL155988-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Yajaira Suarez
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $948,192
- **Award type:** 5
- **Project period:** 2021-01-15 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329985

## Citation

> US National Institutes of Health, RePORTER application 10329985, Insights into the molecular mechanisms regulating vascular and immune metabolism in vascular diseases (5R35HL155988-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10329985. Licensed CC0.

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