Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis.
Aged
Aged, 80 and over
Animals
Arteries
/ metabolism
Atherosclerosis
/ genetics
Cells, Cultured
Disease Models, Animal
Endothelial Cells
/ metabolism
Female
Humans
Intercellular Signaling Peptides and Proteins
/ genetics
Lymphangiogenesis
Lymphatic Vessels
/ metabolism
Male
Mice, Inbred C57BL
Mice, Knockout, ApoE
Middle Aged
Nitric Oxide Synthase Type III
/ genetics
Plaque, Atherosclerotic
Proto-Oncogene Proteins c-akt
/ metabolism
Receptors, G-Protein-Coupled
/ genetics
Signal Transduction
Thrombospondins
/ genetics
Atherosclerosis
LGR4
Lymphangiogenesis
Lymphatic vessel
Nitric oxide
RSPO2
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
25 05 2021
25 05 2021
Historique:
received:
02
03
2020
revised:
16
07
2020
accepted:
30
07
2020
pubmed:
5
8
2020
medline:
27
1
2022
entrez:
5
8
2020
Statut:
ppublish
Résumé
Impaired lymphatic drainage of the arterial wall results in intimal lipid accumulation and atherosclerosis. However, the mechanisms regulating lymphangiogenesis in atherosclerotic arteries are not well understood. Our studies identified elevated levels of matrix protein R-spondin 2 (RSPO2) in atherosclerotic arteries. In this study, we investigated the role of RSPO2 in lymphangiogenesis, arterial cholesterol efflux into lesion-draining lymph nodes (LNs) and development of atherosclerosis. The effect of RSPO2 on lymphangiogenesis was investigated using human lymphatic endothelial cells (LEC) in vitro and implanted Matrigel plugs in vivo. Cellular and molecular approaches, pharmacological agents, and siRNA silencing of RSPO2 receptor LGR4 were used to investigate RSPO2-mediated signalling in LEC. In vivo low-density lipoprotein (LDL) tracking and perivascular blockade of RSPO2-LGR4 signalling using LGR4-extracellular domain (ECD) pluronic gel in hypercholesterolemic mice were utilized to investigate the role of RSPO2 in arterial reverse cholesterol transport and atherosclerosis. Immunoblotting and imaging experiments demonstrated increased RSPO2 expression in human and mouse atherosclerotic arteries compared to non-atherosclerotic controls. RSPO2 treatment inhibited lymphangiogenesis both in vitro and in vivo. LGR4 silencing and inhibition of RSPO2-LGR4 signalling abrogated RSPO2-induced inhibition of lymphangiogenesis. Mechanistically, we found that RSPO2 suppresses PI3K-AKT-endothelial nitric oxide synthase (eNOS) signalling via LGR4 and inhibits activation of the canonical Wnt-β-catenin pathway. ApoE-/- mice treated with LGR4-ECD developed significantly less atherosclerosis compared with control treatment. Finally, increased arterial lymphatic vessel density and improved lymphatic drainage of fluorescently labelled LDL to deep cervical LNs were observed in LGR4-ECD-treated mice. These findings demonstrate that RSPO2 inhibits lymphangiogenesis via LGR4 and downstream impairment of AKT-eNOS-nitric oxide signalling. These results may also inform new therapeutic strategies to promote lymphangiogenesis and improve cholesterol efflux from atherosclerotic arteries.
Identifiants
pubmed: 32750106
pii: 5880581
doi: 10.1093/cvr/cvaa244
pmc: PMC8152716
doi:
Substances chimiques
Intercellular Signaling Peptides and Proteins
0
LGR4 protein, human
0
LGR4 protein, mouse
0
RSPO2 protein, mouse
0
Receptors, G-Protein-Coupled
0
Rspo2 protein, human
0
Thrombospondins
0
NOS3 protein, human
EC 1.14.13.39
Nitric Oxide Synthase Type III
EC 1.14.13.39
Nos3 protein, mouse
EC 1.14.13.39
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1489-1509Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL146954
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL114648
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY029318
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139562
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
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