Lymphatic vessel insufficiency in hypercholesterolemic mice alters lipoprotein levels and promotes atherogenesis.
OBJECTIVE
Lymphatic vessels collect extravasated fluid and proteins from tissues to blood circulation as well as play an essential role in lipid metabolism by taking up intestinal chylomicrons. Previous studies have shown that impairment of lymphatic vessel function causes lymphedema and fat accumulation, but clear connections between arterial pathologies and lymphatic vessels have not been described.


RESULTS
Two transgenic mouse strains with lymphatic insufficiency (soluble vascular endothelial growth factor 3 [sVEGFR3] and Chy) were crossed with atherosclerotic mice deficient of low-density lipoprotein receptor and apolipoprotein B48 (LDLR(-/-)/ApoB(100/100)) to study the effects of insufficient lymphatic vessel transport on lipoprotein metabolism and atherosclerosis. Both sVEGFR3×LDLR(-/-)/ApoB(100/100) mice and Chy×LDLR(-/-)/ApoB(100/100) mice had higher plasma cholesterol levels compared with LDLR(-/-)/ApoB(100/100) control mice during both normal chow diet (16.3 and 13.7 versus 8.2 mmol/L, respectively) and Western-type high-fat diet (eg, after 2 weeks of fat diet, 45.9 and 42.6 versus 30.2 mmol/L, respectively). Cholesterol and triglyceride levels in very-low-density lipoprotein and low-density lipoprotein fractions were increased. Atherosclerotic lesions in young and intermediate cohorts of sVEGFR3×LDLR(-/-)/ApoB(100/100) mice progressed faster than in control mice (eg, intermediate cohort mice at 6 weeks, 18.3% versus 7.7% of the whole aorta, respectively). In addition, lesions in sVEGFR3×LDLR(-/-)/ApoB(100/100) mice and Chy×LDLR(-/-)/ApoB(100/100) mice had much less lymphatic vessels than lesions in control mice (0.33% and 1.07% versus 7.45% of podoplanin-positive vessels, respectively).


CONCLUSIONS
We show a novel finding linking impaired lymphatic vessels to lipoprotein metabolism, increased plasma cholesterol levels, and enhanced atherogenesis.
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Taina
T
Vuorio
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Harri
H
Nurmi
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Karen
K
Moulton
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Jere
J
Kurkipuro
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Marius R
MR
Robciuc
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Miina
M
Ohman
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Suvi E
SE
Heinonen
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Haritha
H
Samaranayake
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Tommi
T
Heikura
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.
Kari
K
Alitalo
From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.V., J.K., S.E.H., H.S., T.H., S.Y.-H.); Wihuri Research Institute and Translational Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (H.N., M.R.R., M.Ö., K.A.); Cardiology Division, Department of Medicine, University of Colorado, Aurora (K.M.); and Gene Therapy Unit (S.Y.-H.) and Research Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland. Seppo.Ylaherttuala@uef.fi.
Seppo
S
Ylä-Herttuala
D000818:Animals; D001055:Apolipoproteins B / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000378:metabolism*; D042601:Lymphatic Vessels / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000502:physiology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology
D001055:Apolipoproteins B; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol; D040321:Vascular Endothelial Growth Factor Receptor-3
atherosclerosis; lipoproteins; lymphatic vessels