Impaired vascular function in small resistance arteries of LOX-1 overexpressing mice on high-fat diet
Birgit Eichhorn1, Gregor Muller, Anja Leuner
1Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, University of Technology, Fetscherstr. 74, D-01307 Dresden, Germany. birgit.eichhorn@tu-dresden.de
Aims:
LOX-1 is a major vascular receptor for oxidized low-density lipoprotein (oxLDL). In this study, we analysed the impact of LOX-1 overexpression and high dietary fat intake on vascular function in small resistance arteries.
Methods And Results:
Relaxation of mesenteric arteries was measured using a wire myograph. Compared with the control group, mice overexpressing LOX-1 on a high-fat diet (FD) had preserved vascular smooth muscle relaxation, but impaired endothelium-dependent relaxation via NO. Vascular NO availability was decreased by exaggerated formation of reactive oxygen species and decreased endothelial NO synthase expression. Endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation via cytochrome P450 metabolites was increased in LOX-1 + FD animals, but did not completely compensate for the loss of NO. Currents of calcium-activated potassium channels with large conductance (BKCa channels) were measured by the voltage-clamp method. The BKCa current amplitudes were not altered in endothelial cells, but highly increased in vascular smooth muscle cells from resistance arteries of LOX-1-overexpressing mice on FD. BK(Ca) currents were activated by low-dose H2O2 and cytochrome P450 metabolites 11,12-EET and 14,15-EET as EDHF in control mice.
Conclusion:
LOX-1 overexpression and FD caused functional changes in endothelial and vascular smooth muscle cells of small resistance arteries.
Insights
Overexpressing the LOX-1 receptor with a high-fat diet impaired nitric oxide-mediated vascular relaxation but increased smooth muscle cell BKCa channel activity in small arteries.
Area of Science:
- Cardiovascular Biology
- Vascular Physiology
- Lipid Metabolism
Background:
- LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) is a key receptor for oxidized LDL in the vasculature.
- High dietary fat intake is a significant risk factor for cardiovascular disease.
- Understanding the interplay between LOX-1 and dietary factors is crucial for vascular health.
Purpose of the Study:
- To investigate the combined effects of LOX-1 overexpression and high-fat diet on the function of small resistance arteries.
- To elucidate the mechanisms underlying changes in vascular tone and signaling pathways.
Main Methods:
- Wire myography was used to assess vascular smooth muscle and endothelium-dependent relaxation in mesenteric arteries.
- Electrophysiological techniques (voltage-clamp) measured ion channel activity in vascular cells.
- Assessed nitric oxide (NO) bioavailability and endothelial NO synthase (eNOS) expression.
Main Results:
- LOX-1 overexpression and high-fat diet preserved smooth muscle relaxation but impaired endothelium-dependent relaxation mediated by NO.
- Reduced NO availability was linked to increased reactive oxygen species and decreased eNOS expression.
- Endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation was increased but did not fully compensate for NO loss.
- Large-conductance calcium-activated potassium (BKCa) channel currents were significantly increased in vascular smooth muscle cells.
Conclusions:
- Combined LOX-1 overexpression and high-fat diet induce significant functional alterations in endothelial and vascular smooth muscle cells of resistance arteries.
- These changes highlight a complex adaptation of vascular function under conditions of altered lipid metabolism and receptor expression.
