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

Christina Caruso; Meredith E Fay; Xiaopo Cheng; Alan Y Liu; Sunita I Park; Todd A Sulchek; Michael D Graham; Wilbur A Lam

doi:10.1016/j.isci.2022.104606

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

iScience. 2022 Jun 15;25(7):104606. doi: 10.1016/j.isci.2022.104606. eCollection 2022 Jul 15.

Authors

Christina Caruso¹, Meredith E Fay^{1

2}, Xiaopo Cheng³, Alan Y Liu⁴, Sunita I Park⁵, Todd A Sulchek⁴, Michael D Graham³, Wilbur A Lam^{1

2}

Affiliations

¹ Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, 412 Emory Children's Center, 2015 Uppergate Drive, Atlanta, GA 30322, USA.
² Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
³ Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ George W. Woodruff School of Mechanical Engineering, Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁵ Department of Pathology, Children's Healthcare of Atlanta, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

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.

Keywords: Biophysics; biological sciences; cell biology; disease; human Physiology; mechanobiology.

Grants and funding

T32 HL139443/HL/NHLBI NIH HHS/United States