Differential impact of familial hypercholesterolemia and combined hyperlipidemia on vascular wall and network remodeling in mice

Abstract

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.

Figure 1

Plasma total cholesterol (Panel A) and triglycerides (Panel B) in C57, ApoE and LDLR mice at 12–13 weeks or 22–23 weeks of age. Data are presented as mean±SEM, n=8 animals for each group. * p<0.05 vs. C57 at that age; † p<0.05 vs. ApoE at that age.

Figure 2

Passive mechanical characteristics of the skeletal muscle resistance arterial wall in C57, ApoE and LDLR mice at 12–13 weeks or 22–23 weeks of age. Data (mean±SEM) are presented for arterial inner diameter (Panel A), arterial outer diameter (Panel B), arterial wall thickness (Panel C), arterial cross sectional wall area (Panel D), wall:lumen ratio (Panel E) and incremental distensibility (Panel D) over a range of increasing intralumenal pressure, n=8 animals for each group. * p<0.05 vs. that strain at 12–13 weeks; † p<0.05 vs. C57 at that age; ‡ p<0.05 vs. ApoE at that age.

Figure 3

Circumferential wall stress versus strain (Panel A) and tangential elastic modulus versus wall stress (Panel B) relationships in passive skeletal muscle resistance arteries from C57, ApoE and LDLR mice at 12–13 weeks or 22–23 weeks of age. Data are presented as mean±SEM, n=8 animals for each group. * p<0.05 vs. that strain at 12–13 weeks; † p<0.05 vs. C57 at that age; ‡ p<0.05 vs. ApoE at that age.

Figure 4

Gastrocnemius muscle microvessel density in C57, ApoE and LDLR mice at 12–13 weeks or 22–23 weeks of age. Data are presented as mean±SEM, n=8 animals for each group. * p<0.05 vs. C57 at that age; † p<0.05 vs. ApoE at that age.

Figure 5

Plasma nitrotyrosine (Panel A), TNF-α (Panel B), IL-1β (Panel C) and MCP-1 (Panel D) in C57, ApoE and LDLR mice at 12–13 weeks or 22–23 weeks of age. Data are presented as mean±SEM, n=8 animals for each group. * p<0.05 vs. C57 at that age; † p<0.05 vs. ApoE at that age.

Figure 6

Data describing the production of nitric oxide (from aortae, Panel A), 6-keto-PGF_1α (from pooled arteries, Panel B) or 11-dehydro-TxB₂ (from pooled arteries, Panel C) of C57, ApoE and LDLR. Data, presented as mean±SEM, are shown in response to application of 10⁻⁴ M methacholine (Panel A) or 10⁻⁶ M arachidonic acid (Panels B and C). n=6 animals for each group, with each n representing either an aorta or pooled arteries from an individual mouse; please see text for details. * p<0.05 vs. C57 at that age; † p<0.05 vs. ApoE at that age.