VLDL receptor deficiency enhances intimal thickening after vascular injury but does not affect atherosclerotic lesion area.
The very low density lipoprotein receptor (VLDLR) has been shown to modulate cell migration and foam cell formation in vitro. This suggests a role for the VLDLR in vascular pathology associated with intimal thickening and atherogenesis. In the present paper both intimal thickening and atherosclerosis were studied using VLDLR knockout and transgenic mouse models. The role of the VLDLR in intimal thickening was established in an in vivo model for vascular injury. A non-restrictive cuff was placed around the femoral artery of VLDLR deficient (VLDLR-/-), heterozygous deficient (VLDLR+/-) and wild type (WT) mice. Intimal thickening was assessed after 3 weeks by determining the intima to media (I/M) volume ratio. Both VLDLR-/- (I/M ratio 42%) and VLDLR+/- (I/M ratio 40%) mice showed a significant increase as compared with WT littermates (I/M ratio 25%). The effect of VLDLR deficiency on atherosclerosis was examined in VLDLR-/- mice on an LDLR deficient (LDLR-/-) background. In addition, we assessed whether increased endothelial VLDLR expression levels affect atherosclerotic lesion formation. Therefore, atherosclerosis was studied in LDLR deficient mice that over express the VLDLR in endothelial cells (PVL, LDLR-/-). Both VLDLR deficiency and endothelial VLDLR over expression did not affect the atherosclerotic lesion size. Interestingly, VLDLR-/-, LDLR-/- mice showed a high incidence of necrosis in both fatty streaks and atherosclerotic plaques as compared with LDLR-/- mice (75 vs. 0% and 76 vs. 45%, respectively). In conclusion, deficiency for the VLDLR profoundly increased intimal thickening after vascular injury.
Tacken
Paul J
PJ
Department of Human and Clinical Genetics, Leiden University Medical Center, PO Box 9503, 2300 RA Leiden, The Netherlands.
Delsing
Dianne J M
DJ
Gijbels
Marion J J
MJ
Quax
Paul H A
PH
Havekes
Louis M
LM
Hofker
Marten H
MH
van Dijk
Ko Willems
KW
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D005263:Femoral Artery / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis / Q000172:deficiency*; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000293:injuries* / Q000378:metabolism*
D011973:Receptors, LDL; D014280:Triglycerides; C036053:VLDL receptor; D002784:Cholesterol