Altered 3D Vascular Architecture and Cerebral Blood Flow in a Mouse Model of TBI

Abstract

It is established in traumatic brain injury (TBI) animal models that the vasculature undergoes loss and recovery. Although past studies have correlated vascular structural alterations with cerebral blood flow (CBF) changes or functional outcome, analysis has largely focused on histological measures of vessel density and diameter. However, it is the 3D organization of cerebral blood vessels that determines the overall capacity of the cerebral circulation to meet the metabolic requirements of the brain. To examine function and 3D organization in the same mouse brain, a methodology was developed combining in vivo Arterial Spin Labeling (ASL) MRI to quantify blood flow under rest and hypercapnia followed by ex vivo 2-photon fluorescence microscopy (2PFM) to quantify 3D vascular structure. Application of this methodology to a controlled cortical impact mouse model of TBI enabled analysis of the evolution of vascular architecture and its relation to blood flow. Despite early (1-day) loss of vasculature, vessel density and vascular volume recovered 1-month post-TBI. However, the reorganized vasculature possessed a radial pattern that corresponded to low blood flow. Since these microvascular alterations are difficult to directly detect with in vivo technologies, ultrasound wave reflection analysis was applied to the carotid arteries of these mice. It was demonstrated that quantification of cerebral vascular resistance with ultrasound has the potential to detect whether a mouse received a TBI. Ultrasound therefore may present an efficient, non-invasive method for detecting TBI via changes in vascular architecture.