Abstract
Maternal physiological or supraphysiological hypercholesterolemia (MPH, MSPH) occurs during pregnancy. MSPH is associated with foetal endothelial dysfunction and atherosclerosis. However, the potential effects of MSPH on placental microvasculature are unknown. The aim of this study was to determine whether MSPH alters endothelial function in the placental microvasculature both ex vivo in venules and arterioles from the placental villi and in vitro in primary cultures of placental microvascular endothelial cells (hPMEC). Total cholesterol < 280 mg/dL indicated MPH, and total cholesterol ≥280 mg/dL indicated MSPH. The maximal relaxation to histamine, calcitonin gene-related peptide and adenosine was reduced in MSPH venule and arteriole rings. In hPMEC from MSPH placentas, nitric oxide synthase (NOS) activity and L-arginine transport were reduced without changes in arginase activity or the protein levels of endothelial NOS (eNOS), human cationic amino acid 1 (hCAT-1), hCAT-2A/B or arginase II compared with hPMEC from MPH placentas. In addition, it was shown that adenosine acts as a vasodilator of the placental microvasculature and that NOS is active in hPMEC. We conclude that MSPH alters placental microvascular endothelial function via a NOS/L-arginine imbalance. This work also reinforces the concept that placental endothelial cells from the macro- and microvasculature respond differentially to the same pathological condition.
Highlights
Maternal levels of total cholesterol (TC) increase as human pregnancy progresses, i.e., maternal physiological hypercholesterolemia in pregnancy (MPH), to satisfy the demand of this lipid by the growing foetus[1]
This study shows for first time that increased levels of maternal TC and low-density lipoprotein cholesterol (LDL) in maternal supraphysiological hypercholesterolemia in pregnancy (MSPH) are associated with endothelial dysfunction of the human placental microvasculature, likely due to an imbalance between nitric oxide synthases (NOS) activity and L-arginine transport
The percentage of inhibition of maximal dilation in response to histamine, CGRP and adenosine was determined in the presence of NG-nitro-L-arginine methyl ester (L-NAME, 100 μmol/L, 30 min) in MPH (d) and MSPH (e) venules and arterioles. (f) Dilation in response to sodium nitroprusside (10 μmol/L, 5 min) in vessels from MPH or MSPH placentas
Summary
Maternal levels of total cholesterol (TC) increase as human pregnancy progresses, i.e., maternal physiological hypercholesterolemia in pregnancy (MPH), to satisfy the demand of this lipid by the growing foetus[1]. MSPH and increased maternal LDL levels are associated with endothelial dysfunction of the umbilical vein[1,3,4,5] and early development of atherosclerosis in the foetal aorta[6,7]. In human umbilical vein endothelial cells (HUVEC) isolated from MSPH pregnancies, reduced NOS activity, increased endothelial L-arginine uptake, and increased expression and activity of arginase II have been reported[3,5]. It has been proposed that MSPH could be a crucial condition that increases the risk of an adverse foetal outcome and risk of developing cardiovascular diseases later in life[1,15,16] In this scenario, the role of the placenta and the consequences of MSPH on the endothelial function of the placental microvasculature are still unknown. The aim of this work was to determine the effects of MSPH on endothelial function in small vessels of the placenta ex vivo in microvenules and arterioles from the placental villi as well as in vitro in primary cultures of placental microvascular endothelial cells
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