Introduction

Cerebral vasospasm can be defined in terms of angiographic findings or clinical signs. Ecker and Riemenschneider first described angiographic vasospasm in 1951 (1). Angiographic vasospasm can be detected in up to 70% of patients following subarachnoid hemorrhage (SAH) (2). Clinically, cerebral vasospasm usually starts 3 to 5 days following SAH, exhibits maximal narrowing between days 5 and 14, and gradually resolves over 2 to 4 weeks (3). Clinical cerebral vasospasm, or neurologic deterioration due to cerebral ischemia, is less common and develops in 20% to 30% of patients with SAH.

Because the time course of clinical cerebral vasospasm parallels that of angiographic vasospasm and clinical symptoms often improve following intra-arterial injections of vasodilators or balloon angioplasty, clinical vasospasm is thought to be the result of persistent narrowing of the arterial lumen of the major extraparenchymal arteries. The extent of angiographic vasospasm in the proximal cerebral circulation, therefore, has been used as the most important outcome measure in animal models of the disease. However, infarctions on CT scans of patients with vasospasm typically occur in multiple territories, and the correlation between the severity of angiographic narrowing and clinical vasospasm is not entirely clear. Mounting evidence suggests that vascular proliferation may play an important additional role in the development of delayed cerebral ischemia through altered cerebral vascular compliance and cerebral autoregulation changes (4-7).

The volume of the subarachnoid clot is the only consistently demonstrated risk factor for vasospasm, and it is widely accepted that the pathogenic stimuli responsible for vasospasm are released from the blood clot (8). However, less agreement exists regarding the exact nature of these factors and the signaling pathways and mechanisms involved in the pathogenesis of vasospasm. Current evidence suggests that vasospasm is probably the result of prolonged pathologic arterial constriction of sensitized vessels. With time, arteries that are exposed to subarachnoid blood become less compliant and less responsive to vasodilator therapy. These changes coincide with progressive structural changes within all of the layers of the vessel wall, closely resembling the vascular remodeling response to injury in other disease states. In common with other forms of vascular remodeling, proposed mechanisms include inflammation, free radicals and oxidative stress, and endothelial dysfunction, resulting in intracellular signaling perturbations of the protein kinase, nitric oxide (NO), and, possibly, other pathways. Endothelial dysfunction and injury may alter the normal balance between vasoconstrictor and vasodila-tory mechanisms. Once disturbed, the contraction mechanism of the vessels may be sensitized or upregulated, resulting in exaggerated or even paradoxical vasoconstriction. Furthermore, vascular injury may result in abnormal vessel wall thickening due to accelerated smooth muscle cell proliferation and collagen deposition. The summation of these events may result in decreased regional cerebral oxygen delivery and ischemic deficits.

Vessels are comprised of living tissues with complex, biochemical functions. Smooth muscle cells (SMCs), which reside in the medial layer, not only provide a motor to control vessel tone but also fulfill a host of other functions: proliferation, chemotaxis, adhesion, secretion, and various metabolic functions (9). In addition, great redundancy and overlap exist in signaling pathways that control these functions. Therefore, both the actions of vasoconstrictors (e.g., endothelin, angiotensin, and catecholamines) and the consequences of inhibiting endogenous vasodilators (e.g., NO) include vascular proliferation. Likewise, the effects of vasodilator therapy, such as calcium channel blockade, which has been shown to improve outcome without reducing

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