The results indicate that long-term hypercholesterolemia combined with high levels of sEng leads to the aggravation of endothelial and vessel wall dysfunction in aorta, with possible alterations of the membrane endoglin/eNOS signaling, suggesting that high levels of soluble endoglin might be considered as a risk factor of cardiovascular diseases.

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Our objective was to investigate the effect of cholesterol [hypercholesterolemia and 7‐ketocholesterol (7K)] on endoglin (Eng) expression and regulation with respect to endothelial or vascular dysfunction in vivo and in vitro. In vivo experiments were performed in 2‐mo‐old atherosclerosis‐prone apolipoprotein E–deficient/LDL receptor–deficient (ApoE−/−/LDLR−/−) female mice and their wild‐type C57BL/6J littermates. In in vitro experiments, human aortic endothelial cells (HAECs) were treated with 7K. ApoE−/−/LDLR−/− mice developed hypercholesterolemia accompanied by increased circulating levels of P‐selectin and Eng and a disruption of NO metabolism. Functional analysis of the aorta demonstrated impaired vascular reactivity, and Western blot analysis revealed down‐regulation of membrane Eng/Smad2/3/eNOS signaling in ApoE−/−/LDLR−/− mice. 7K increased Eng expression via Krüppel‐like factor 6 (KLF6), liver X nuclear receptor, and NF‐&x03BA;B in HAECs. 7K‐induced Eng expression was prevented by the treatment with 2‐hydroxypropyl‐β‐cyclodextrin; 8‐{[5‐chloro‐2‐(4‐methylpiperazin‐1‐yl) pyridine‐4‐carbonyl] amino}‐1‐(4‐fluorophenyl)‐4, 5‐dihydrobenzo[g]indazole‐3‐carboxamide; or by KLF6 silencing. 7K induced increased adhesion and transmigration of monocytic human leukemia promonocytic cell line cells and was prevented by Eng silencing. We concluded that hypercholesterolemia altered Eng expression and signaling, followed by endothelial or vascular dysfunction before formation of atherosclerotic lesions in ApoE−/−/LDLR−/− mice. By contrast, 7K increased Eng expression and induced inflammation in HAECs, which was followed by an increased adhesion and transmigration of monocytes via endothelium, which was prevented by Eng inhibition. Thus, we propose a relevant role for Eng in endothelial or vascular dysfunction or inflammation when exposed to cholesterol.—Vicen, M., Vitverova, B., Havelek, R., Blazickova, K., Machacek, M., Rathouska, J., Najmanová, I., Dolezelova, E., Prasnicka, A., Sternak, M., Bernabeu, C, Nachtigal, P. Regulation and role of endoglin in cholesterol‐induced endothelial and vascular dysfunction in vivo and in vitro. FASEB J. 33, 6099–6114 (2019). http://www.fasebj.org

Aims: A soluble form of endoglin (sEng) was proposed to participate in the induction of endothelial dysfunction in small blood vessels. Here, we tested the hypothesis that high levels of sEng combined with a high-fat diet induce endothelial dysfunction in an atherosclerosis-prone aorta. Methods and Results: Six-month-old female and male transgenic mice overexpressing human sEng (Sol-Eng⁺) with low (Sol-Eng⁺low) or high (Sol-Eng⁺high) levels of plasma sEng were fed a high-fat rodent diet containing 1.25% cholesterol and 40% fat for 3 months. The plasma cholesterol and mouse sEng levels did not differ in the Sol-Eng⁺high and Sol-Eng⁺low mice. The expression of proinflammatory (P-selectin, ICAM-1, pNFκB and COX-2) and oxidative-stress-related markers (HO-1, NOX-1 and NOX-2) in the aortas of Sol-Eng⁺high female mice was significantly higher than in Sol-Eng⁺low female mice. Endothelium-dependent vasodilatation induced by acetylcholine was preserved better in the Sol-Eng⁺ high female mice than in the Sol-Eng⁺low female mice. Conclusion: These results suggest that high concentrations of sEng in plasma in combination with a high-fat diet induce the simultaneous activation of proinflammatory, pro-oxidative and vasoprotective mechanisms in mice aorta and the balance of these biological processes determines whether the final endothelial phenotype is adaptive or maladaptive.