Hemodynamic and Histological Effects of Traumatic Brain Injury in eNOS-Deficient Mice

Abstract

Microvascular dysfunction in the brain, characterized by vasoconstriction, vascular occlusion, and disruption of the blood brain barrier, may adversely affect outcome following traumatic brain injury (TBI). Because of its vasodilating and antiaggregative properties, nitric oxide (NO) produced by nitric oxide synthase in the endothelium (eNOS) is a key regulator of vascular homeostasis. The objective of the present study was to evaluate the role of eNOS in vascular disturbances and histological outcome in the brain following TBI. Cortical blood flow ([(14)C]-iodoantipyrine technique), number of perfused capillaries (FITC-dextran technique), brain water content (wet vs. dry weight), and the transfer constant (K(i)) for [(51)Cr]-EDTA, reflecting permeability, were analyzed 3 h and 24 h after a controlled cortical impact injury (CCI) in eNOS-deficient (eNOS-KO) and wild-type (WT) mice. Cortical contusion volume and cell count in the hippocampus were evaluated 3 weeks after injury. Blood flow in the injured cortex decreased in both groups following trauma. There were no significant differences between the groups at 3 h, but blood flow was lower in eNOS-KO mice than in WT mice 24 h after trauma. Brain water content was higher in the WT mice than in eNOS-KO mice at 24 h. Number of perfused capillaries, K(i), and histological outcome were similar in both groups. We conclude that eNOS is important for maintenance of cerebral blood flow after trauma and that eNOS promotes edema formation by mechanisms other than increased permeability. The vascular effects of eNOS do not, however, influence histological outcome.

Endothelial Nitric Oxide Modulates Expression and Processing of Amyloid Precursor Protein

“…While additional studies are required to determine the exact contribution of hypertension and insulin resistance to the elevation of Aβ our in vitro data indicate that loss of endothelial NO is sufficient to increase APP, BACE1 and Aβ levels in the absence of any hemodynamic forces or insulin resistance. In addition, existing evidence suggests that hypoperfusion can lead to alterations in brain APP and Aβ levels; however, prior reports demonstrated that cerebral blood flow is normal in eNOS −/− animals17, 18.…”

The role of the nitric oxide pathway in brain injury and its treatment — From bench to bedside

“…The immunoreactivity of eNOS is increased in the area surrounding the contused area in the first 3 days after experimental trauma (Cobbs et al, 1997). eNOS knockout mice have greater reduction in CBF than wild type variants in the first 2 h after trauma (Lundblad et al, 2009). Genetic variants of eNOS influence the maintenance of CBF after severe TBI.…”

Fresh Frozen Plasma Resuscitation Provides Neuroprotection Compared to Normal Saline in a Large Animal Model of Traumatic Brain Injury and Polytrauma

“…Further, reports from murine models have indicated that inhalation of NO after TBI is neuroprotective and reduces cerebral inflammation, 23,24 whereas other reports have indicated that eNOS-deficient mice have lower cerebral blood flow than wild-type mice after cortical impact. 18 In contrast to this, other reports have linked high brain microdialysate levels of NO to adverse outcome after TBI, 25 whereas results from a murine cortical impact model reported reduced brain edema formation in eNOSdeficient mice. 24 Although these results may seem conflicting, it is likely that TBI-induced dysregulation of the balance between vasoconstrictors, such as ET-1, and vasodilators, such as eNOS and NO, promotes development of the secondary brain injury by inducing local hypoxia through compromised cerebral perfusion.…”

“…This is likely primarily owing to superior plasma volume expansion and reduced cerebral edema in the FFP group, contrasted with rapid fluid extravasation into the brain parenchyma in the NS group. Alternatively, the observed favorable brain oxygenation profile in the FFP group may, in part, be associated with an endothelial preservation resulting in better vasomotor control through mediators such as eNOS, 18 with subsequent improvements in cerebral perfusion pressures and brain oxygenation.…”