EphB3 signaling induces cortical endothelial cell death and disrupts the blood–brain barrier after traumatic brain injury

Abstract

Damage to the cerebrovascular network is a major contributor to dysfunction in patients suffering from traumatic brain injury (TBI). Vessels are composed of lumen-forming endothelial cells that associate closely with both glial and neuronal units to establish a functional blood–brain barrier (BBB). Under normal physiological conditions, these vascular units play important roles in central nervous system (CNS) homeostasis by delivering oxygen and nutrients while filtering out molecules and cells that could be harmful; however, after TBI this system is disrupted. Here, we describe a novel role for a class of receptors, called dependence receptors, in regulating vessel stability and BBB integrity after CCI injury in mice. Specifically, we identified that EphB3 receptors function as a pro-apoptotic dependence receptor in endothelial cells (ECs) that contributes to increased BBB damage after CCI injury. In the absence of EphB3, we observed increased endothelial cell survival, reduced BBB permeability and enhanced interactions of astrocyte-EC membranes. Interestingly, the brain’s response to CCI injury is to reduce EphB3 levels and its ligand ephrinB3; however, the degree and timing of those reductions limit the protective response of the CNS. We conclude that EphB3 is a negative regulator of cell survival and BBB integrity that undermine tissue repair, and represents a protective therapeutic target for TBI patients.

Angiopoietin/Tie2 Axis Regulates the Age-at-Injury Cerebrovascular Response to Traumatic Brain Injury

“…It is therefore plausible that increased GFAP immunoreactivity may represent overzealous astrogliosis in the juvenile cortex following acute CCI injury, which may potentiate the positive effects of reactive astrocytes. Although astrocytes are important regulators of tissue recovery, there is a two-way exchange of signals between ECs and astrocytes (Goldstein, 1987;Estrada et al, 1990;Spoerri et al, 1997;Wagner and Gardner, 2000;Mi et al, 2001;Abbott, 2002;Engelhardt and Liebner, 2014;Wang et al, 2016a). In what way this bidirectional relationship is affected following TBI and whether the age-at-injury EC response alters EC-astrocyte communication is unclear.…”

“…Although physical trauma to the developing brain may interrupt the maturation of key developmental processes that support higher-order cognition in adulthood, numerous studies support an age-related difference in early functional recovery. Several human studies demonstrate that increased age negatively influences outcome with the greatest amount of improvement in disability was seen in early adolescent patients (Marquez de la Plata et al, 2008), whereas children under 2 years of age represent a high-risk group with poorer outcome (Adelson et al, 1997). These findings are supported by preclinical studies in swine demonstrating greater lesion formation with increased age after acute cortical impact injury (Duhaime et al, 2003;Missios et al, 2009).…”

“…However, in addition to the well described evolution of chronic injury following juvenile TBI, there is evidence of acute tissue protection compared with adults in several swine models (Duhaime et al, 2000(Duhaime et al, , 2003. Age-related differences in the cerebrovascular response has been suggested to play a role (Adelson et al, 1997;Armstead, 1999;Durham et al, 2000;Claus et al, 2010;Curvello et al, 2017). Preserving adequate vascularization, tone, and function can minimize the loss of oxygen and nutrient supply as well as prevent buildup of metabolic waste after TBI (Fitzgerald et al, 2010;Salehi et al, 2017).…”

Ephs and Ephrins in Adult Endothelial Biology

“…In addition, the administration of ephrinB3 in a mouse injury model resulted in less apoptosis of cortical vascular endothelial cells and a less dramatic decrease in vessel density after injury. However, knockout of the EphB3 receptor rendered similar results and, therefore, the EphB3 receptor was described to function as a pro-apoptotic dependence receptor, where ligand binding or receptor knockout is necessary to prevent EphB3 from inducing cellular apoptosis [56]. On the other hand, the knockdown of the ephrinB1 and ephrinB3 ligands in endothelial cells induced apoptosis and ephrinB1 even selectively more in senescent cells compared to nonsenescent cells [57].…”

“…For example, the increased vascular permeability observed in different forms of induced lung injury in mice could be reduced by an EphA2 knockout, administration of recombinant EphA2 or EphA2 receptor blocking antibodies [39,96,97]. The breakdown of the blood-brain-barrier after traumatic brain injury or induced by cerebral malaria in mice, also marked by increased vascular leakage, could be prevented by knockout of EphB3 [56] or EphA2, respectively [75], while the induction of Eph signaling by administration of ephrinA1 after ischemia/reperfusion injury induced blood-brain-barrier damage. These ephrinA1-treated mice showed more inflammation and edema in the brain and had decreased neurological scores.…”