Role for Tetrahydrobiopterin in the Fetoplacental Endothelial Dysfunction in Maternal Supraphysiological Hypercholesterolemia

Maternal physiological hypercholesterolemia occurs during pregnancy, ensuring normal fetal development. In some cases, the maternal plasma cholesterol level increases to above this physiological range, leading to maternal supraphysiological hypercholesterolemia (MSPH). This condition results in endothelial dysfunction and atherosclerosis in the fetal and placental vasculature. The fetal and placental endothelial dysfunction is related to alterations in the L-arginine/nitric oxide (NO) pathway and the arginase/urea pathway and results in reduced NO production. The level of tetrahydrobiopterin (BH4), a cofactor for endothelial NO synthase (eNOS), is reduced in nonpregnant women who have hypercholesterolemia, which favors the generation of the superoxide anion rather than NO (from eNOS), causing endothelial dysfunction. However, it is unknown whether MSPH is associated with changes in the level or metabolism of BH4; as a result, eNOS function is not well understood. This review summarizes the available information on the potential link between MSPH and BH4in causing human fetoplacental vascular endothelial dysfunction, which may be crucial for understanding the deleterious effects of MSPH on fetal growth and development.

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Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00328.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. C1181-C1192 ◽

Cited By ~ 78

Author(s):

Alia Shatanawi ◽

Maritza J. Romero ◽

Jennifer A. Iddings ◽

Surabhi Chandra ◽

Nagavedi S. Umapathy ◽

...

Keyword(s):

Angiotensin Ii ◽

Endothelial Dysfunction ◽

P38 Mapk ◽

Gene Knockout ◽

Rho Kinase ◽

Arginase Activity ◽

No Production ◽

Vascular Endothelial ◽

Ang Ii ◽

Vascular Endothelial Dysfunction

Enhanced vascular arginase activity impairs endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (ANG II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. We determined signaling mechanisms by which ANG II increases endothelial arginase function. Results show that ANG II (0.1 μM, 24 h) elevates arginase activity and arginase I expression in bovine aortic endothelial cells (BAECs) and decreases NO production. These effects are prevented by the arginase inhibitor BEC (100 μM). Blockade of ANG II AT1 receptors or transfection with small interfering RNA (siRNA) for Gα12 and Gα13 also prevents ANG II-induced elevation of arginase activity, but siRNA for Gαq does not. ANG II also elevates active RhoA levels and induces phosphorylation of p38 MAPK. Inhibitors of RhoA activation (simvastatin, 0.1 μM) or Rho kinase (ROCK) (Y-27632, 10 μM; H1152, 0.5 μM) block both ANG II-induced elevation of arginase activity and phosphorylation of p38 MAPK. Furthermore, pretreatment of BAECs with p38 inhibitor SB-202190 (2 μM) or transfection with p38 MAPK siRNA prevents ANG II-induced increased arginase activity/expression and maintains NO production. Additionally, inhibitors of p38 MAPK (SB-203580, 5 μg·kg−1·day−1) or arginase (ABH, 8 mg·kg−1·day−1) or arginase gene knockout in mice prevents ANG II-induced vascular endothelial dysfunction and associated enhancement of arginase. These results indicate that ANG II increases endothelial arginase activity/expression through Gα12/13 G proteins coupled to AT1 receptors and subsequent activation of RhoA/ROCK/p38 MAPK pathways leading to endothelial dysfunction.

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Protective Effects and Mechanisms of Vaccarin on Vascular Endothelial Dysfunction in Diabetic Angiopathy

International Journal of Molecular Sciences ◽

10.3390/ijms20184587 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4587 ◽

Cited By ~ 6

Author(s):

Fei Xu ◽

Yixiao Liu ◽

Xuexue Zhu ◽

Shuangshuang Li ◽

Xuelin Shi ◽

...

Keyword(s):

Endothelial Cell ◽

Endothelial Dysfunction ◽

Early Stage ◽

Biological Activities ◽

Vascular Endothelial Cell ◽

Microvascular Endothelial Cell ◽

No Production ◽

Vascular Endothelial ◽

Vascular Endothelial Dysfunction ◽

Compound C

Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.

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