Abstract
Signaling pathways of red blood cells’ (RBCs) micromechanics regulation, which are responsible for maintaining microcirculation, constitute an important property of RBC physiology. Selective control over these processes may serve as an indispensable tool for correction of hemorheological disorders, which accompany a number of systemic diseases (diabetes mellitus I&II, arterial hypertension, malaria, etc.). Activation of certain pathways involving adenylyl cyclase may provide fast adaptive regulation of RBC deformability (RBC-D). However the specific molecular conditions of intracellular signal transduction in mediating RBC microrheological properties at adenylyl cyclase stimulation remain unclear. In this paper, we present the results of the in vitro study of the effects of different signaling pathways in adenylyl cyclase stimulation on RBC-D. We studied (1) the direct stimulation of adenylyl cyclase with forskolin; (2) non-selective adrenoreceptor stimulation with epinephrine; (3) β2-adrenoreceptor agonist metaproterenol; (4) membrane-permeable analog of cAMP (dibutyryl-cAMP). Using laser ektacytometry, we observed a concentration-dependent increase in RBC-D for all studied effectors. The EC50 values for each substance were estimated to be in the range of 1–100 μM depending on the shear stress applied to the RBC suspension. The results can serve as an evidence of adenylyl cyclase signaling cascade involvement in the regulation of RBC micromechanical properties presenting a complex molecular pathway for fast increase of microcirculation efficiency in case of corresponding physiologic metabolic demands of the organism, e.g., during stress or physical activity. Further studies of this molecular system will reveal new knowledge which may improve the quality of medical treatment of hemorheological disorders.
Highlights
Human red blood cells (RBCs) are highly specialized cells
Hemorheological disorders, which accompany a number of systemic diseases such as diabetes mellitus I&II, arterial hypertension, sickle cell decease, etc. are characterized with a dramatic decrease in RBC deformability (RBC-D), leading to the impairment of blood perfusion, which may result in irreversible tissue necrosis (Barshtein et al, 2007)
Change in laser diffraction pattern was measured by recording the signal designated as elongation index (EI) as a function of shear stress
Summary
Human red blood cells (RBCs) are highly specialized cells. Their main function is to provide transport of respiration gases and various metabolic nutrients in organs and tissues. RBCs preserved many elements of molecular signaling cascades which allow fast adaptive regulation of microrheological properties in response to metabolic requirements of the organism (Takakuwa et al, 1990; Muravyov et al, 2009; Muravyov and Tikhomirova, 2013; Richou et al, 2018). Triggers of such systems are various signaling molecules: catecholamines (epinephrine and norepinephrine), adrenoreceptor agonists (adrenomimetics), and hormones; effectors of ion channels and pumps. The data on the mechanisms of NO export from RBC into the blood stream as well as its effects on RBC microrheology are very contradictory and being very intensively studied (Singel and Stamler, 2004; Ulker et al, 2018; Sun et al, 2019)
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