Motivation
Blood vessels are commonly damaged as a result of both accidental trauma and surgical manipulation, but little is known about the mechanics of this damage or how damage processes affect subsequent vessel function, particularly when damage is subtle.
Traumatic brain injury (TBI) is a devastating cause of death and disability, claiming approximately 1.7 million victims each year in the United States alone, many of which die or suffer debilitating neurologic deficits (see the CDC TBI page). The cerebral vessels play an important role in the maintenance of the healthy brain. Although damage to brain tissue is the fundamental concern in TBI, nearly all significant cases include some element of injury to the blood vessels, and any injury or dysfunction of the vasculature puts neural tissue at risk. Hemorrhage and other vascular dysfunction are common sequelae of both conventional TBI and blast injury. Recent clinical studies have identified TBI as a risk factor for stroke, comparable in significance to hypertension, the leading risk factor. Stroke is a similarly devastating disease of the cerebral vessels. Despite the identified relationship between TBI and stroke, mechanisms for their association remain unknown, but dysfunction of cerebral vessels that have not properly healed from the preceding TBI event may contribute.
Atherosclerosis is the primary cause of vascular disease and commonly manifests in cerebral vessels as ischemic stroke, a leading cause of death and disability in industrialized nations. Diseased arteries are limited in their ability to deliver needed blood flow due to plaque formation, and emboli may be released from plaque sites, resulting in occlusions downstream. Surgery and angioplasty are two commonly used procedures to restore flow in stenotic arteries when medical treatment is not effective. Historically, surgery has been considered to be more reliable, but angioplasty is becoming an equally viable alternative, especially considering its relatively non-invasive nature. Angioplasty aims to reduce stenosis by expanding a vessel beyond its elastic limits. This expansion disrupts the endothelium, alters the fibrous proteins of the extracellular matrix (ECM), and often damages any plaque present. Despite these acute alterations, blood flow is usually restored successfully, though restenosis is common, and it is not clear that vessels fully recover from the induced damage. Guidelines on balloon expansion are limited, since relationships between vessel stretch and recovery have not been quantified. As a consequence, each interventionalist performs the procedure differently based on their training.
In both TBI and angioplasty, little attention is paid to vessel damage. The prevailing clinical approach is to assume that a vessel is fine if it isn’t bleeding. This strategy appears to be effective at a basic level, but our research shows that even minor damage significantly alters function. We anticipate that improved understanding of damage mechanisms and their effects on vessel function will stimulate much-needed progress in injury prevention and treatment and in the optimization of medical procedures that induce vascular damage.
Research Areas
Characterization of damage to the cerebral vessel wall as a result of large deformations is an area of recent particular current interest for our laboratory. It is well known that cerebral blood vessels are often torn and bleed as an immediate consequence of TBI. It follows that other vessels experience deformations that are significant but not severe enough to produce bleeding. Little is known about the prognosis of these injured cerebral vessels and their potential contribution to subsequent disease progression, but our research shows that both mechanical properties and microstructure, including collagen fibers in the vessel wall and the internal elastic lamina, are damaged as a consequence of overstretch. Our research also shows that vessel regulatory function is altered by overstretch ex vivo. More work needs to be done to better understand the initiation and evolution of these changes in vivo, but it seems clear that understanding vessel damage in TBI is of fundamental importance in guiding therapy development.
The development of models for study of blood vessel damage is critical to answer questions related to in vivo injury. Because brain injury is the primary concern in TBI, relatively little attention has been given to injury of the vasculature, but it is clear that brain tissue is at risk when blood vessels are damaged. Our work investigating such injury in response to mild blast exposure in the rat demonstrated a diffuse distribution of small BBB lesions. Current work is following up on this, but this type of subtle injury may be responsible for symptoms of mild TBI seen in soldiers returning from the battlefield. More conventional loading achieved using controlled cortical impact suggests that fluid entrapment may play a role in cortical penetrating vessels disruption. We have also characterized the response of cerebral vessels from animals, such as rats and sheep, to allow interpretation of vascular injury in these systems relative to the human.
Defining the mechanical response of cerebral blood vessels is one focus of my research efforts. It has long been known that cerebral vessels commonly rupture and bleed as a consequence of head trauma, but the mechanisms of these injuries and their thresholds of occurrence have not been defined, nor has the role of the vessels in the response of surrounding brain tissue been described. Computer models provide an opportunity to answer these questions and to define relationships between exterior loads and sites of expected injury, but properties needed to define vessel response in these models have not been available. Our experiments have provided this needed data and have shown that fresh human cerebral arteries are approximately three orders of magnitude stiffer than the brain parenchyma alone. They are also particularly stiff and withstand significantly less stretch prior to failure in comparison to both cerebral veins and vessels elsewhere in the circulation. Our research further shows that the properties of these vessels are not dependent on strain rates below 500/s. We have also defined vessel failure values and characterized them through development.
Vessel response to non-damaging loads is another area of interest for our group. The threshold of loading at which damage occurs is currently unknown, but there is evidence that vessel homeostatic function is altered under minor loads of various types. A deeper understanding of such alterations may open doors for potential therapeutic strategies that manipulate the vessel wall in one way or another. Our work in this area has shown that vessel permeability can be manipulated by various applications of ultrasound, providing needed data for localized drug delivery. We’ve also shown that changes in flow lead to transient alterations of mechanical properties that correlate with expression of matrix metalloproteinase (MMP). No previous work has shown that vessels mechanics can be altered so quickly and transiently or that MMP expression produces a measurable temporary decrease in vessel stiffness.
External Funding
(Current and Previous)
- Centers for Disease Control & Prevention (National Center for Injury Prevention & Control)
- Department of Defense
- Henry Jackson Foundation
- National Institutes of Health (National Institute for Child Health & Human Development)
- National Science Foundation
- Primary Children’s Medical Center Foundation
- Utah Research Foundation