Maternal Smoking Highly Affects the Function, Membrane Integrity, and Rheological Properties in Fetal Red Blood Cells

Abstract

An understanding of the basic pathophysiological mechanisms of neonatal diseases necessitates detailed knowledge about the wide range of complications in the circulating fetal RBCs. Recent publications on adult red blood cells (RBCs) provide evidence that RBCs carry an active nitric oxide synthase (NOS3) enzyme and contribute to vascular functioning and integrity via their active nitric oxide synthesis. The aim of this study was to determine the effect of maternal smoking on the phenotypical appearance and functionality of fetal RBCs, based on morphological and molecular studies. We looked for possible links between vascular dysfunction and NOS3 expression and activation and its regulation by arginase (ARG1). Significant morphological and functional differences were found between fetal RBCs isolated from the arterial cord blood of neonates born to nonsmoking (RBC-NS, n = 62) and heavy-smoking (RBC-S, n = 51) mothers. Morphological variations were quantified by Advanced Cell Classifier, microscopy-based intelligent analysis software. To investigate the relevance of the newly suggested “erythrocrine” function in fetal RBCs, we measured the levels of NOS3 and its phosphorylation in parallel with the level of ARG1, as one of the major influencers of NOS3 dimerization, by fluorescence-activated cell sorting. Fetal RBCs, even the “healthy-looking” biconcave-shaped type, exhibited impaired NOS3 activation in the RBC-S population, which was paralleled with elevated ARG1 level, thus suggesting an increased redox burden. Our molecular data indicate that maternal smoking can exert marked effects on the circulating fetal RBCs, which could have a consequence on the outcome of in utero development. We hypothesize that any endothelial dysfunction altering NO production/bioavailability can be sensed by circulating fetal RBCs. Hence, we are putting forward the idea that neonatal RBC could serve as a real-time sensor for not only monitoring RBC-linked anomalies but also predicting the overall status of the vascular microenvironment.

Sustained Maternal Smoking Triggers Endothelial-Mediated Oxidative Stress in the Umbilical Cord Vessels, Resulting in Vascular Dysfunction

“…Significantly lower head and chest circumference values (6–6.5%) were measured in cases of neonates born to smoking mothers. The birthweight-based distribution was even more characteristic: 55% of neonates in the control group had a birthweight above 3500 g, while only 13% of neonates with smoking origin reached this value [ 16 ].…”

“…In that study we pointed out that in fetal RBCs with smoking origin, the NOS3-NO pathway is unavailable as a rescue mechanism in case of vascular dysfunction. Furthermore, we proved that the maternal-smoking-induced ARG1 expression in Sm-RBCs may even augment the vascular dysfunction and serve as the etiology for cardiovascular diseases [ 16 , 47 ].…”

“…In the case of reduced NOS3-dependent NO production / bioavailability, alternative NO producing pathways get activated as compensatory mechanisms to improve the blood flow to the fetus. The vessel endothelium is in continuous contact with circulating red blood cells (RBCs), and, moreover, an intimate crosstalk between them was recently reported under pathological conditions [ 16 , 17 ]. Supposing that ED can be sensed by circulating RBCs, NO bioavailability might be increased by the RBC-NOS3 activation pathway.…”

“…However, our previous studies on the maternal and fetal RBCs indicated significant alterations in the RBCs’ morphological parameters, elastic and plastic properties and abnormalities in their membrane-lipid composition, along with an impaired NOS3 activation, as the consequence of maternal smoking. All these alterations make it most likely that the NOS3-dependent NO production by RBCs is not available as a compensatory mechanism [ 16 , 18 , 19 ]. Another obvious solution for compensation could be the upregulation of inducible nitric oxide synthase (NOS2) expression in the endothelial layer, due to its high (100–1000 fold that of NOS3) catalytic activity and/or the activation of xanthine oxidoreductase (XOR) [ 20 , 21 ].…”

Erratum to “Maternal Smoking Highly Affects the Function, Membrane Integrity, and Rheological Properties in Fetal Red Blood Cells”

“…In the article titled “Maternal Smoking Highly Affects the Function, Membrane Integrity, and Rheological Properties in Fetal Red Blood Cells” [ 1 ], there was an error in Figure 3. The figure should show a single cell image with 5 μ m scale bar.…”