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Mechanisms of Cholesterol Induced Lymphatic Dysfunction: Can GLP-1R Agonism Improve Lymphatic Function in Obesity and Metabolic Syndrome?

Award Number: R01HL185906
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Mechanisms of Cholesterol Induced Lymphatic Dysfunction: Can GLP-1R Agonism Improve Lymphatic Function in Obesity and Metabolic Syndrome? - PROJECT SUMMARY Lymphedema is a chronic, debilitating disease affecting >250 million people worldwide with no pharmacological therapies available. Our group and others have demonstrated a reciprocal connection between obesity and lymphatic system dysfunction. In the U.S., the largest group of patients afflicted with lymphedema are cancer survivors, who develop lymphatic disease following cancer treatments. Obesity increases the risk of lymphedema development by >3-fold in these patients. Therefore, there is a critical need to develop pharmacological therapeutics to treat, prevent, or reduce the risk of developing lymphedema. Collecting lymphatic vessels rely on the intrinsic contractility of lymphatic muscle cells (LMCs) and intraluminal one-way valves to move fluid forward. We previously demonstrated valve dysfunction in collecting lymphatic vessels from diet-induced obese (DIO) wild-type (WT) mice, whereas vessels from hypercholesterolemic DIO ApoE-deficient (DIO-ApoEKO) mice displayed severe contractile and valve dysfunction, as well as hyperpermeability; however, the mechanisms by which high cholesterol exacerbates lymphatic dysfunction in obesity remain largely unexplored. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as effective therapies to reduce body weight and help lower cholesterol. Recent clinical studies suggested these may be effective alternatives to treat or reduce the risk of developing lymphedema in breast cancer patients; however, whether this is associated with a lymphatic-specific effect of GLP-1R agonism remains unknown. Our preliminary findings showed that lymphatic vessels from lean ApoEKO mice displayed mitochondrial electron transport chain defects, increased superoxide levels, and upregulation of the ubiquitin-proteasome system in lymphatic endothelial cells (LECs), and impaired contractility of collecting lymphatics and concomitant dysregulation of contractile proteins in LMCs, which may be partially associated with crosstalk with perivascular macrophages by dysregulated cytokine signaling. In addition, in collecting lymphatic vessels and surrounding areas, GLP-1Rs were exclusively detected in LECs and significantly downregulated in lymphatics from lean ApoEKO mice compared with controls. Furthermore, the GLP-1R agonist, Semaglutide, significantly improved the contractile capacity of lymphatics from healthy and obesity-induced dysfunctional lymphatics from mice and non-human primates. This application will test the following aims: 1) determine the specific role of LEC-GLP-1Rs in regulating the function of collecting lymphatics and metabolic dysfunction in obesity; and identify novel molecular mechanisms of lymphatic dysfunction associated with hypercholesterolemia; and 2) assess the ability of GLP-1R agonism to improve the function of collecting lymphatic vessels in obesity and hypercholesterolemia and identify the underlying molecular mechanism. We anticipate that our findings will provide the critical preclinical evidence for the potential use of GLP-1R agonists to treat obesity-induced lymphatic dysfunction, as well as uncover additional underlying mechanisms. We will also generate the first comprehensive scRNAseq dataset of human lymphatic vessels.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $499,736 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	1	8/15/2026	NEW	$499,736
														Subtotal = $499,736

Grand Total All Awards = $499,736

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Mechanisms of Cholesterol Induced Lymphatic Dysfunction: Can GLP-1R Agonism Improve Lymphatic Function in Obesity and Metabolic Syndrome?

Award Number: R01HL185906

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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