Differential impact of familial hypercholesterolemia and combined hyperlipidemia on vascular wall and network remodeling in mice.
Genetic familial hypercholesterolemia (FH) and combined hyperlipidemia (FCH) are characterized by elevated plasma low-density lipoprotein (LDL) (FH) and LDL/triglycerides (FCH), with mouse models represented by LDL receptor (LDLR) and apolipoprotein E (ApoE) gene deletion mice, respectively. Given the impact of FH and FCH on health outcomes, we determined the impact of FH/FCH on vascular structure in LDLR and ApoE mice. LDLR, ApoE and control mice were utilized at 12-13 and 22-23 weeks when gracilis arteries were studied for wall mechanics and gastrocnemius muscles were harvested for microvessel density measurements. Conduit arteries and plasma samples were harvested for biochemical analyses. Arteries from ApoE and LDLR exhibited blunted expansion versus control, reduced distensibility and left-shifted stress versus strain relation (LDLR > ApoE). Microvessel density was reduced in ApoE and LDLR (ApoE > LDLR). Secondary analyses suggested that wall remodeling in LDLR was associated with cholesterol and MCP-1, while rarefaction in ApoE was associated with tumor necrosis factors-alpha, triglycerides and vascular production of TxA(2). Remodeling in ApoE and LDLR appears distinct; as that in LDLR is preferential for vascular walls, while that for ApoE is stronger for rarefaction. Remodeling in LDLR may be associated with cellular adhesion, while that in ApoE may be associated with pro-apoptotsis and constrictor prostanoid generation.
Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
Phoebe A
PA
Stapleton
Adam G
AG
Goodwill
Milinda E
ME
James
Alexandre C
AC
D'Audiffret
Jefferson C
JC
Frisbee
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D016718:Arachidonic Acid / Q000378:metabolism; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006938:Hyperlipoproteinemia Type II / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply; D009569:Nitric Oxide / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
D001057:Apolipoproteins E; D011973:Receptors, LDL; D016718:Arachidonic Acid; D009569:Nitric Oxide