Effects of LDL Receptor Modulation on Lymphatic Function.
Atherosclerosis is driven by the accumulation of immune cells and cholesterol in the arterial wall. Although recent studies have shown that lymphatic vessels play an important role in macrophage reverse cholesterol transport, the specific underlying mechanisms of this physiological feature remain unknown. In the current report, we sought to better characterize the lymphatic dysfunction that is associated with atherosclerosis by studying the physiological and temporal origins of this impairment. First, we assessed that athero-protected Pcsk9(-/-) mice exhibited improved collecting lymphatic vessel function throughout age when compared to WT mice for up to six months, while displaying enhanced expression of LDLR on lymphatic endothelial cells. Lymphatic dysfunction was present before the atherosclerotic lesion formation in a mouse model that is predisposed to develop atherosclerosis (Ldlr(-/-); hApoB100(+/+)). This dysfunction was presumably associated with a defect in the collecting lymphatic vessels in a non-specific cholesterol- but LDLR-dependent manner. Treatment with a selective VEGFR-3 agonist rescued this impairment observed early in the onset of this arterial disease. We suggest that LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction, and bring forth a pleiotropic role for PCSK9 in lymphatic function. Our study unveils new potential therapeutic targets for the prevention and treatment of atherosclerosis.
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.|Montreal Heart Institute, Montreal, Quebec, Canada.
Andreea
A
Milasan
Montreal Heart Institute, Montreal, Quebec, Canada.
François
F
Dallaire
Laboratory of Molecular Cell Biology, Montreal Heart Institute Research Center, Quebec, Canada.|Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada.
Gaétan
G
Mayer
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.|Montreal Heart Institute, Montreal, Quebec, Canada.
Catherine
C
Martel
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
D011973:Receptors, LDL; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9