Sex-specific contribution of endothelial AT1aRs to avoidance behaviors and BBB changes in a mouse model of PTSD

Posttraumatic stress disorder (PTSD) affects more than 9% of the population, and currently FDA-approved treatments show limited efficacy. There is therefore an urgent need to better understand the underlying pathophysiological mechanisms in order to identify new therapeutic strategies. Recent evidence implicates a role of angiotensin II (Ang II) signaling in PTSD symptomatology, yet the mechanisms through which Ang II contributes to trauma-related pathology remain unclear. We hypothesized that endothelial angiotensin type 1a receptors (AT_1aR) is a key player in psychological trauma-induced changes in blood-brain barrier (BBB) integrity, systemic and central inflammation, as well as PTSD-like symptoms. To test this hypothesis, we used the predator trauma model of PTSD in male and female wild-type (WT) mice and mice with an endothelial-specific depletion of AT_1aR (eAT_1aR^-/-). One week later, anxiety-like and avoidance behaviors were assessed, and brain tissues were collected to evaluate BBB integrity and neuroinflammation. Both male and female eAT_1aR^-/- mice exhibited reduced generalized anxiety-like behavior, while avoidance behavior was selectively attenuated in males, independently of trauma exposure. Trauma-induced changes in cortical expression of the tight junction protein zonula occludens-1 were not affected by endothelial AT_1aR deletion, whereas claudin-5 expression in the prefrontal cortex was increased in predator-exposed eAT_1aR^-/- females. Together, these findings provide the first evidence that endothelial Ang II-AT_1aR signaling modulate basal levels of anxiety-like and avoidance behaviors independently of trauma exposure, while also regulating trauma-induced changes in BBB integrity in a sex-dependent manner. These results suggest that endothelial AT_1aR signaling does not underlie the trauma-induced behavioral and immune phenotypes, but nonetheless highlight AT1Rs as a novel target for anxiolytic therapeutics.