Pathologic mechanobiological interactions between red blood cells and endothelial cells directly induce vasculopathy in iron deficiency anemia

• Type of Material: Article
• Authors: Christina Caruso, Emory University; Meredith E Fay, Emory University; Xiaopo Cheng, University of Wisconsin Madison; Alan Y Liu, Georgia Institute of Technology; Sunita Park, Emory University; Todd A Sulchek, Georgia Institute of Technology; Michael D Graham, University of Wisconsin Madison; Wilbur Lam, Emory University
• Language: English
• Date: 2022-06-27
• Publisher: CELL PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Author(s).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.isci.2022.104606
• Title of Journal or Parent Work: ISCIENCE
• Volume: 25
• Issue: 7
• Start Page: 104606
• End Page: 104606
• Grant/Funding Information: This work was supported by an American Society of Hematology (ASH) Research Training Award for Fellows (RTAF), National Institutes of Health, Institute of Heart, Lung, and Blood (NIH NHLBI) grant T32HL139443 and Pediatric Loan Repayment Program (LRP) Award L40HL149069 (C.C.), National Institutes of Health, Institute of Heart, Lung, and Blood (NIH NHLBI) grants R01HL140589 and R35HL145000 (W.A.L.), and National Science Foundation grant CBET-2042221 (X.C. and M.D.G.).
• Keywords: DEFORMABILITY; Science & Technology - Other Topics; FLOW; Science & Technology; Multidisciplinary Sciences

Abstract

The correlation between cardiovascular disease and iron deficiency anemia (IDA) is well documented but poorly understood. Using a multi-disciplinary approach, we explore the hypothesis that the biophysical alterations of red blood cells (RBCs) in IDA, such as variable degrees of microcytosis and decreased deformability may directly induce endothelial dysfunction via mechanobiological mechanisms. Using a combination of atomic force microscopy and microfluidics, we observed that subpopulations of IDA RBCs (idRBCs) are significantly stiffer and smaller than both healthy RBCs and the remaining idRBC population. Furthermore, computational simulations demonstrated that the smaller and stiffer idRBC subpopulations marginate toward the vessel wall causing aberrant shear stresses. This leads to increased vascular inflammation as confirmed with perfusion of idRBCs into our “endothelialized” microfluidic systems. Overall, our multifaceted approach demonstrates that the altered biophysical properties of idRBCs directly lead to vasculopathy, suggesting that the IDA and cardiovascular disease association extends beyond correlation and into causation.