Sustained maternal smoking-associated changes in the physico-chemical properties of fetal RBC membranes might serve as early markers for vascular comorbidities

Abstract

Maternal smoking-induced congenital heart and microvascular defects are closely associated with the impaired functioning of the in-utero feto-placental circulation system. Current groundbreaking facts revealed intimate crosstalk between circulating red blood cells (RBCs) and the vascular endothelium. Thus, RBCs have become the protagonists under varied pathological and adverse pro-oxidative cellular stress conditions. We isolated and screened fetal RBCs from the arterial cord blood of neonates, born to non-smoking (RBC-NS) and smoking mothers (RBC-S), assuming that parameters of fetal RBCs are blueprints of conditions experienced in-utero. Using atomic force microscopy and mass spectrometry-based shotgun lipidomics in the RBC-S population we revealed induced membrane stiffness, loss in intrinsic plastic activities and several abnormalities in their membrane-lipid composition, that could consequently result in perturbed hemodynamic flow movements. Altogether, these features are indicative of the outcome of neonatal microvascular complications and suggest unavailability for the potential rescue mechanism in cases of vascular endothelium impairment due to altered membrane integrity and rheological properties.

Molecular Background of Toxic-Substances-Induced Morphological Alterations in the Umbilical Cord Vessels and Fetal Red Blood Cells

“…Based on a recent publication, there is an active communication between the vessel endothelium and RBCs, where any functional alterations in the RBCs have an impact on the endothelial status [ 21 ]. One of the possible intermediary agents in the circulated RBCs could be the accumulated peroxynitrite, a highly reactive nitrogen species, formed spontaneously from O 2 •− and NO [ 50 ]. Peroxynitrite-dependent cytotoxicity on the one hand relies on its ability to trigger lipid peroxidation in membranes, resulting in an increased level of reactive aldehyde, 4-HNE.…”

A terhesség alatti dohányzással összefüggésbe hozható endotéliális diszfunkció molekuláris vizsgálata köldökzsinór modellrendszerben

“…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 modifications /alterations, make it is most likely, that the NOS3-dependent NO production by RBCs is not available as a compensatory mechanism 251,253,254 . 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 the NOS3) catalytic activity and/or the activation of xanthine oxidoreductase (XOR) 158,255 .…”

“…Ezért a méhen belüli állapotok megváltozása közvetlenül vagy közvetett módon kapcsolódnak a placenta vagy a köldökzsinór olyan rendellenességeihez, mint az intrauterin hypoxia és az elégtelen magzati vérellátás [72][73][74] . Emellett egy nemrégiben publikált kemo-biológiai interaktóm analízis megerősítette, és bizonyítékot szolgáltatott arra, hogy a dohányfüst komponensei intenzíven befolyásolják a génexpressziót mind embrionális, mind pedig a magzati fejlődési időszakban 96 Az eredmények így azt valószínűsítik, hogy a VVT-k NOS3-függő NO termelése nem érvényesülhet kompenzációs mechanizmusként 251,253,254 . A kompenzáció másik kézenfekvő megoldása az indukálható nitrogén-oxid-szintáz (NOS2) expressziójának növekedése az endotheliális rétegben, mivel katalitikus aktivitása (100-1000-szerese a NOS3-nak) 255 .…”