Endothelial expression of endoglin in normocholesterolemic and hypercholesterolemic C57BL/6J mice before and after atorvastatin treatment

Abstract

Endoglin (CD105) is a homodimeric transmembrane glycoprotein strongly related to transforming growth factor (TGF)-beta signaling and many pathological states. In this study, we wanted to evaluate whether endoglin is expressed in normocholesterolemic and hypercholesterolemic C57BL/6J mice as well as whether it is affected by atorvastatin treatment in these mice. C57BL/6J mice were fed with chow diet or an atherogenic diet for 12 weeks after weaning. In 2 atorvastatin-treated groups, mice were fed the same diets (chow or atherogenic) as described above except atorvastatin was added at the dosage of 10 mg x kg(-1) x day(-1) for the last 8 weeks before euthanasia. Biochemical analysis of blood samples revealed that administration of atherogenic diet significantly increased levels of total cholesterol, VLDL, LDL, and decreased levels of HDL. Atorvastatin treatment resulted in a significant decrease in total cholesterol and VLDL only in mice fed by atherogenic diet. Quantitative stereological analysis revealed that atorvastatin significantly decreased endothelial expression of endoglin in C57BL/6J mice fed the atherogenic diet. In conclusion, we demonstrated that endothelial expression of endoglin is upregulated by hypercholesterolemia and decreased by the hypolipidemic effect of atorvastatin in C57BL/6J mice, suggesting that endoglin expression could be involved in atherogenesis.

Atorvastatin Increases Endoglin, SMAD2, Phosphorylated SMAD2/3 and eNOS Expression in ApoE/LDLR Double Knockout Mice

“…We found only a weak expression of endoglin inside atherosclerotic plaque and almost no expression by smooth muscle cells in vessel media. These results are consistent with our previous studies of non-atherosclerotic vessels in normoand hypercholesterolemic mice 7,22) suggesting that endoglin is expressed predominantly by the vessel endothelium in mice. This discrepancy with previous studies in humans might reflect the differences between human and mice atherogenesis.…”

“…In contrast, in our previous study we found that atorvastatin decreased endoglin expression by both hypolipidemic and pleiotropic effects 6,7) ; however, there are some substantial differences when we compare with the results of this study. Firstly, the previous study used different mouse strains, apoE-deficient 6) and C57BL/6J mice 7) .…”

“…The primary sequence of human endoglin is composed of an extracellular domain of vation and translocation of the SMAD family of proteins to the nucleus to participate in regulating gene expression 5) . We previously demonstrated that endoglin is expressed by the aortic vessel endothelium in normo-and hypercholesterolemic mice 6,7) . Moreover, endoglin expression was also detected in human and porcine atherosclerotic lesions 3,4,8) .…”

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

“…Our previous study focused on endothelial expression of endoglin in the aorta where no atherosclerosis was detected, demonstrating reduced endoglin expression after statin treatment 45) . Moreover, pitavastatin treatment suppressed Angiotensin -induced enhancement of cardiac TGF-1 expression and Smad2/3 signaling and prevented fibrotic changes 46) .…”

“…It must be stated that direct evidence of this working pathway is complicated due to some limitations of in vivo experiments. In general, it is complicated to precisely explain endoglin participation in the regulation of the proposed pathways and atherosclerosis in vivo because endoglin is exclusively expressed in endothelial cells in mice 4,45) , while other members of the cascade, including ALK, Smad proteins and VEGF, are also expressed in the whole vessel wall. Other authors also showed increased endoglin expression in smooth muscle cells, and in macrophages in human and porcine atherosclerotic lesions 8,18) .…”