Erythroid Transient Receptor Potential vanilloid-1: An Essential Component of Red Blood Cell Rheology, Brain Oxygenation, and Cerebral Circulation After Traumatic Brain Injury

Introduction: Cerebral hypoxia and loss of re-oxygenation, secondary to global and regional changes in cerebral blood flow and loss of erythroid rheology are clinically associated with increased morbidity and mortality after traumatic brain injury (TBI). This loss of rheology is due to erroneous erythropoesis and leads to high expression of membranous Transient receptor potential vanilloid (TRPV-1). Given the role of calcium in RBC deformation, we hypothesized that modulation of TRPV-1, a cation channel and pain receptor causes calcium influx in RBCs, and leads to loss of function by RBCs after TBI.

Methods: We utilized moderate controlled-cortical impact model of mice for TBI. A craniotomy was made in the right parietal bone and brain was impacted at 3 m/s to mimic a moderate to severe TBI. Cerebral blood flow was measured by Vevo Lazr-X. Mice were sacrificed at 5th or 7th day post-injury, blood was collected, fixed for electron microscopy and imaging. Flow analysis were performed.

Results: We observed lower number of mature RBCs in injured mice, while TBI induced significantly higher number of immature precursors cells in circulation in comparison to sham (p < 0.01). TBI induced higher expression of HBB, GPA, TRPV-1 membranous proteins during erythropoiesis while sham mice showed basal levels of expression (p < 0.05). Immuno-label RBCs showed high number of PIRT cells after TBI as compared to sham (p < 0,001), suggesting and important role of PIRT in RBC deformability.

Conclusion : TBI mice showed higher number of deformed RBCs. The TBI mice also expressed high TRPV1 and Phosphoinositide Interacting Regulator of TRP Channels (PIRT), which mirrored loss of their elasticity, micro-thrombi formation, restricted cerebral blood flow and therefore lack of cerebral oxygenation. Our results demonstrate a key role for erythroid TRPV1-PIRT in regulation of hypoxia and vaso-occlusion and may provide a therapeutic target and biomarker for loss of oxygenation and long-term TBI outcome.