# Insulin regulation of lymphatic vessel integrity

> **NIH NIH R56** · SAINT LOUIS UNIVERSITY · 2022 · $366,522

## Abstract

PROJECT SUMMARY/ABSTRACT
Integrity of lymphatic vessels enables maintenance of organ function and protective immunity. The role of lipid
metabolism in lymphatic development and maintenance is now emerging, but less is known about how the lipid
milieu regulates lymphatic vessel integrity. Lipid and insulin signaling are associated with abnormal endothelial
function but targets of lipid and insulin signaling in the lymphatics are understudied. Lipids affect endothelial
cellular homeostasis through protein modifications such as lipidation. Emerging studies show that insulin
regulates endothelial lipidation of proteins relevant to vascular integrity and remodeling. Whether this regulation
applies to endothelial cells of lymphatic origin remain unexplored. Lymphatic endothelial cells have higher
sensitivity to insulin than blood endothelial cells but physiological relevance remains unclear. Lymphatic
endothelial insulin resistance could impair LEC homeostasis and function, however in vivo verification is
necessary in the prospect of clinical translation.
Our studies showed an unexpected higher expression of the lipid translocase CD36 in collecting lymphatic
vessels. Loss of CD36 in lymphatic endothelial cells compromises vessel integrity and causes multi-organ
inflammation typical of endothelial dysfunction. Insulin and CD36 are mutually regulated in many cell types. We
hypothesize that insulin-mediated regulation of CD36 post-translational modifications and turnover regulates
lymphatic vessel integrity. Toward this goal, we aim to examine the novel regulation of lymphatic vessel integrity
and the contribution of impaired insulin signaling to dysfunctional lymphatic vessels. We will identify new targets
of insulin-mediated lipidation in lymphatic vessels and address whether loss of CD36 skews phenotypic and
functional heterogeneity of LEC subsets in the mesenteric collecting vessels promoting an inflammatory,
profibrotic, and metabolically abnormal phenotype. Our study will uncover the cross-talk between lymphatic
vascular function and commensal microbiota, and reveal organ-specific and systemic effects of dysfunctional
lymphatics. We will then evaluate whether transient ablation of the microbiota, or dietary intervention improves
lymphatic integrity and could ameliorate metabolic outcomes and inflammation.

## Key facts

- **NIH application ID:** 10683800
- **Project number:** 1R56HL165199-01
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Vincenza Cifarelli
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $366,522
- **Award type:** 1
- **Project period:** 2022-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683800

## Citation

> US National Institutes of Health, RePORTER application 10683800, Insulin regulation of lymphatic vessel integrity (1R56HL165199-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10683800. Licensed CC0.

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