Faculty Collaboration Database

Downregulation of low-density lipoprotein receptor mRNA in lymphatic endothelial cells impairs lymphatic function through changes in intracellular lipids. Theranostics 2022;12(3):1440-1458

Date

02/15/2022

Pubmed ID

35154499

Pubmed Central ID

PMC8771568

DOI

10.7150/thno.58780

Scopus ID

2-s2.0-85122672999 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

Rationale: Impairment in lymphatic transport is associated with the onset and progression of atherosclerosis in animal models. The downregulation of low-density-lipoprotein receptor (LDLR) expression, rather than increased circulating cholesterol level per se, is involved in early atherosclerosis-related lymphatic dysfunction. Enhancing lymphatic function in Ldlr^-/- mice with a mutant form of VEGF-C (VEGF-C 152s), a selective VEGFR-3 agonist, successfully delayed atherosclerotic plaque onset when mice were subsequently fed a high-fat diet. However, the specific mechanisms by which LDLR protects against lymphatic function impairment is unknown. Methods and results: We have thus injected wild-type and Pcsk9^-/- mice with an adeno-associated virus type 1 expressing a shRNA for silencing Ldlr in vivo. We herein report that lymphatic contractility is reduced upon Ldlr dowregulation in wild-type mice only. Our in vitro experiments reveal that a decrease in LDLR expression at the mRNA level reduces the chromosome duplication phase and the protein expression of VEGFR-3, a membrane-bound key lymphatic marker. Furthermore, it also significantly reduced the levels of 18 lipid subclasses, including key constituents of lipid rafts as well as the transcription of several genes involved in cholesterol biosynthesis and cellular and metabolic processes. Exogenous PCSK9 only reduces lymphatic endothelial-LDLR at the protein level and does not affect lymphatic endothelial cell integrity. This puts forward that PCSK9 may act upon lymphatic muscle cells to mediate its effect on lymphatic contraction capacity in vivo. Conclusion: Our results suggest that treatments that specifically palliate the down regulation of LDLR mRNA in lymphatic endothelial cells preserve the integrity of the lymphatic endothelium and sustain lymphatic function, a prerequisite player in atherosclerosis.

Author List

Vachon L, Smaani A, Tessier N, Jean G, Demers A, Milasan A, Ardo N, Jarry S, Villeneuve L, Alikashani A, Finherty V, Ruiz M, Sorci-Thomas MG, Mayer G, Martel C

Author

Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Atherosclerosis
Cholesterol
Down-Regulation
Endothelial Cells
Hyperlipidemias
Lipids
Lipoproteins, LDL
Mice
Mice, Inbred C57BL
Mice, Knockout
Proprotein Convertase 9
RNA, Messenger
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor Receptor-3