Blast-induced phenotypic switching in cerebral vasospasm

Abstract

Vasospasm of the cerebrovasculature is a common manifestation of blast-induced traumatic brain injury (bTBI) reported among combat casualties in the conflicts in Afghanistan and Iraq. Cerebral vasospasm occurs more frequently, and with earlier onset, in bTBI patients than in patients with other TBI injury modes, such as blunt force trauma. Though vasospasm is usually associated with the presence of subarachnoid hemorrhage (SAH), SAH is not required for vasospasm in bTBI, which suggests that the unique mechanics of blast injury could potentiate vasospasm onset, accounting for the increased incidence. Here, using theoretical and in vitro models, we show that a single rapid mechanical insult can induce vascular hypercontractility and remodeling, indicative of vasospasm initiation. We employed high-velocity stretching of engineered arterial lamellae to simulate the mechanical forces of a blast pulse on the vasculature. An hour after a simulated blast, injured tissues displayed altered intracellular calcium dynamics leading to hypersensitivity to contractile stimulus with endothelin-1. One day after simulated blast, tissues exhibited blast force dependent prolonged hypercontraction and vascular smooth muscle phenotype switching, indicative of remodeling. These results suggest that an acute, blast-like injury is sufficient to induce a hypercontraction-induced genetic switch that potentiates vascular remodeling, and cerebral vasospasm, in bTBI patients.neurotrauma | mechanotransduction | tissue engineering | vascular mechanics

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

“…We fabricated stretchable muscular thin film (MTF) substrates by selectively coating silicone membranes with a temperature-sensitive polymer and a thin layer of polydimethylsiloxane (PDMS; Fig. 1A) (23)(24)(25), building on previous efforts of Zhuang et al (26) and Yamada et al (27). Substrates micropatterned with fibronectin (FN) in a "brick wall" pattern ( Fig.…”

A Threshold Shear Force for Calcium Influx in an Astrocyte Model of Traumatic Brain Injury

“…[14][15][16]50 In astrocytes, injury-induced Ca 2 + elevation has been studied using a stretching model and Ca 2 + variations have been reported to last for minutes to hours. 18,19 We do not know the messenger pathways and effectors that are modulating this response at these slow time scales. Further, different stimuli-stretching or fluid shear-may change severity and types of injury.…”

“…Because astrocytes have cationic mechanosensitive ion channels (MSCs) that are permeable to Ca 2 + , 12,14,15 mechanical stimuli (stretching or shear forces) can activate them and cause an increase in intracellular Ca 2 + . 16 However, most studies have been conducted by stretching flexible substrates with adherent cultured cells [17][18][19] or with fluid shear forces that are much slower than the shockwaves that produce TBI. 18,20 Little is known about the coupling of intracellular Ca 2 + responses to blast-like shear force in astrocytes.…”

Molecular force transduction by ion channels – diversity and unifying principles

“…In this approach, however, one is pulling on focal cell adhesions and this stress is being passed onto the cytoskeleton through the adhesion complexes and an unknown fraction spreads into the bilayer (Alford et al, 2011). The bilayer is a liquid and it will flow under a tension gradient so its tension tends to be uniform.…”