Small blood vessel disease after TBI
Using our animal models, we have shown that traumatic brain injury can induce effects on tissue beds both near and far from the initial site of damage, through mechanisms including changes in reactive oxygen species, endothelial nitric oxide production, and calcium signals. We discovered that changes in cerebrovascular function after TBI involve a paradoxical, gain-of endothelial-induced vasodilatory function, caused by induction of iNOS in the vascular endothelium. In addition, we obtained convincing evidence of endothelial dysfunction in the systemic microvasculature following TBI, with data that explains the underlying mechanism. Unlike the cerebral arteries, which have increased NO levels and a loss of vasodilatory tone, we found that similar-sized systemic arteries from the mesenteric microcirculation have decreased NO levels, decreased NO or vasodilatory response to agonists, and increased endothelial arginase-2. Recently, we have generated data showing that traumatic brain injury impacts the function of the endothelial inward rectifier potassium channel, in both systemic and cerebral small blood vessels in both the brain and systemic circulation, through a mechanism which appears to involve disruption of phosphatidylinositol 4,5-bisphosphate metabolism.
Current experiments funded by the Department of Defense have allowed us to expand our work to include the study of blood flow and vascular responses in the brains of TBI mice in vivo with multi-photon microscopy, in collaboration with Dr. Mark Nelson’s laboratory (embed link to Nelson Lab).
- Larson BA, Stockwell D, Boas S, Andrews T, Wellman G, Lockette W, Freeman K. Cardiac reactive oxygen species after traumatic brain injury. J of Surgical Research (2012 Apr;173(2):e73-81). PMID: 22172132
- Moody BJ, Liberman C, Zvara P, Smith PP, Freeman K and Zvarova K: Acute lower urinary tract dysfunction (LUTD) following traumatic brain injury (TBI) in rats. Neurourology & Urodynamics; (2014 Sep;33(7):1159-64). PMID: 24038177
- Villalba N, Sonkusare SK, Longden TA, Tran TL, Nelson MT, Wellman GC, Freeman K. Traumatic brain injury disrupts cerebrovascular tone through endothelial iNOS expression and nitric oxide gain-of-function. Journal of the American Heart Association (2014; 2014 Dec 19;3(6). PMID: 25527626
- Villalba N, Sackheim A, Nunez I, Hill-Eubanks D, Nelson MT, Wellman GC, Freeman K. Traumatic brain injury causes endothelial dysfunction in the systemic microcirculation through arginase-1-dependent uncoupling of endothelial nitric oxide synthase. Journal of Neurotrauma. (2017; Jan 1;34(1):192-203.) PMID: 26757855 (Featured on cover of the journal).