Neuroscience Graduate Program
Oregon Health & Science University
Subarachnoid Hemorrhage (SAH) is a devastating form of stroke caused by rupture of a large cerebral artery. This catastrophic event is associated with high mortality and long term neurological disability. SAH is also associated with other complications, which are severe and common. The complications are biphasic in nature, with some appearing very early after ictus such as acute hydrocephalus and cerebral edema, while others manifest days later; for example, delayed cerebral ischemia (DCI). The mechanisms underlying these complications are poorly understood but growing evidence suggests that dysfunction of the cerebral microvasculature plays a significant role in their development. The work in this thesis will first seek to characterize one of the earliest causes of impaired microvascular perfusion after SAH related to impaired CSF flow. Second, this work will study changes in the epoxyeicosanoid pathway in humans after SAH and then test its role as a protective mechanism in both early and delayed microvascular dysfunction.
Blood entering the cerebrospinal fluid (CSF) space is a primary pathology in SAH. The protein, cellular and ionic content of the blood are all capable of disrupting normal brain function. Fibrinogen is the third most abundant protein found in the blood and key component of the hemostatic system. In experimental SAH, I found that blood, containing fibrinogen, flows into CSF spaces within minutes following SAH induction in the mouse. This fibrinogen forms an insoluble barrier within the CSF flow spaces, blocking CSF flow and leading to elevated intracranial pressure (ICP), which compresses underlying cortical tissue and impairs cortical perfusion. Clearance of fibrin with tissue plasminogen activator (tPA) 1 hour after SAH restores CSF flow in the mouse, lowers ICP and improves cortical perfusion within 24 hours. Lowering ICP without clearing fibrin deposits does not have the same effect on cortical perfusion. Thus, blockade of CSF flow leads to impaired microvascular blood flow after SAH in an ICP dependent and ICP independent manner.
Delayed cerebral ischemia (DCI) is a common and life threatening complication of SAH that commonly occurs between 3-14 days after vessel rupture. It has been well documented that the eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) plays a xviii
detrimental role in DCI after SAH, but little is known about the role of epoxyeicosatrienoic acids (EETs), which are vasodilators in the microcirculation. In SAH patients, I found that CSF levels of both 20-HETE and 14,15-EET are elevated after SAH and those with the highest concentrations of both are more likely to experience DCI than those with lower concentrations. SAH in mice causes immediate vasoconstriction of pial arteries and delayed decreases in microvascular perfusion. Genetically modified mice with higher levels of 14,15-EET, due to deletion of its metabolizing enzyme soluble epoxide hydrolase (sEH), also exhibit pial artery constriction, but are nonetheless protected from microvascular perfusion deficits after SAH. Thus, both 20-HETE and 14,15-EET are increased after SAH. Although 20-HETE may contribute to DCI, 14,15-EET plays a protective role against delayed microvascular perfusion deficits and may represent a therapeutic target in SAH.
Early complications of SAH include acute hydrocephalus and global cerebral edema, both of which contribute to poor outcome after SAH. EETs have potent anti-inflammatory effects that may serve a protective role in these early complications. In mice with SAH, I found that acute communicating hydrocephalus develops within hours of hemorrhage induction. Cerebral edema and brain swelling also occur early after SAH and lead to disruption of the cortical white matter. Mice with genetically elevated levels of EETs are not protected from hydrocephalus but have reduced cerebral edema and less disruption of the white matter. Mice with higher levels of EETs also have better behavioral outcome than wild type mice.
Collectively, these results show that a component of the extravasated blood, fibrinogen, is capable of causing microvascular dysfunction within minutes of SAH by blocking CSF flow. The EETs pathway is activated after SAH and represents an important therapeutic target for treating both early and delayed complications of SAH.
School of Medicine
Siler, Dominic A., "Mechanisms of microvascular dysfunction following subarachnoid hemorrhage" (2014). Scholar Archive. 3548.