Sickle cell mice exhibit elevated plasma bilirubin and altered intracranial cerebral blood velocities that are exacerbated by hypoxia-reoxygenation

Francisco J Nunez; Ashraf M Mohieldin; Amy Y Pan; Sean P Palecek; Rahima Zennadi; Ramani Ramchandran; Kevin R Rarick; Surya M Nauli

doi:10.1177/0271678X251338961

Sickle cell mice exhibit elevated plasma bilirubin and altered intracranial cerebral blood velocities that are exacerbated by hypoxia-reoxygenation

J Cereb Blood Flow Metab. 2025 May 15:271678X251338961. doi: 10.1177/0271678X251338961. Online ahead of print.

Authors

Francisco J Nunez¹, Ashraf M Mohieldin², Amy Y Pan³, Sean P Palecek⁴, Rahima Zennadi⁵, Ramani Ramchandran⁶, Kevin R Rarick⁷, Surya M Nauli¹

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, USA.
² College of Graduate Studies, Master Program of Pharmaceutical Science, California Northstate University, Elk Grove, CA, USA.
³ Division of Quantitative Health Sciences, Department of Pediatrics, CRI, Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ Department of Chemical and Biological Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI, USA.
⁵ Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
⁶ Developmental Vascular Biology Program, Division of Neonatology, Department of Pediatrics, Children's Research Institute (CRI), Medical College of Wisconsin, Milwaukee, WI, USA.
⁷ Division of Critical Care, Department of Pediatrics, CRI, Medical College of Wisconsin, Milwaukee, WI, USA.

PMID: 40370318
DOI: 10.1177/0271678X251338961

Abstract

Sickle cell disease (SCD) is a genetic disorder characterized by sickle red blood cells (RBCs). Sickle RBCs cause cerebral vasculopathies including vaso-occlusive events, leading to ischemia-reperfusion injury and hypoxic tissue environment. To date, the physiological blood flow velocities in cerebral vessels of preclinical SCD models has not been evaluated under hypoxic-reoxygenation. In our study, we used transcranial ultrasound techniques to measure abnormal blood flow velocities in the internal carotid (ICA) and middle cerebral arteries (MCA) of transgenic sickle cell mice (SS) challenged with hypoxia-reoxygenation. Our study showed that SS mice that underwent hypoxic stress exhibited lower relative mean velocities in the MCA compared to wildtype mice (AA) (0.67 ± 0.18 vs. 0.95 ± 0.15; p < 0.05). Comparison of the Lindegaard ratio between normoxia and hypoxia in SS mice suggested that the MCA underwent vasodilation (0.67 ± 0.18 vs. 0.95 ± 0.15; p < 0.05). Bilirubin, a potential biomarker for cerebral vasculopathies in SCD, was higher in SS than AA mice (0.56 $\pm$ 0.28 vs. 0.05 $\pm$ 0.07 mg/dL; p < 0.05). Correlation analyses revealed a significant association between bilirubin levels and blood velocities of MCA (r = -0.9377, p = 0.0002) and ICA (r = 0.8203, p = 0.0068), especially in hypoxic conditions of SS mice. We propose that the reactivity of cerebral vessels in SS mice is correlated with the elevated plasma bilirubin level.

Keywords: Blood flow; cerebral; cilia; intracranial; ultrasound.