Since its recognition over 40 years ago, cerebral vasospasm after subarachnoid hemorrhage (SAH) has remained an enigma to clinicians. The basic mechanisms of arterial narrowing after subarachnoid hemorrhage remain largely undiscovered and current treatments are mostly palliative. Even the term cerebral vasospasm may be imprecise, as controversy exists regarding the role and timing of active vasoconstriction as a cause of decreased vessel caliber. SAH affects over 30,000 Americans annually; in most contemporary series, 15% of such patients suffer stroke or death from vasospasm with maximal therapy. Despite advances in diagnosis and treatment, cerebral vasospasm remains the greatest treatable cause of morbidity and mortality in patients who survive the ictus of SAH. The unifying hypothesis of this proposal is that delayed arterial narrowing after prolonged exposure to perivascular blood occurs in two phases: 1) an initial active phase characterized by reversible, calcium-dependent vasoconstriction, and 2) a subsequent passive phase which is reversible by vasodilators and calcium-independent. Oxyhemoglobin released from peri- arterial thrombus after SAH likely participates in both phases by 1) initial vasoconstriction and 2) subsequent phenotypic changes in cerebral arterial smooth muscle and endothelium, most likely due to cytotoxic injury from lipid peroxidation. The phenotype of injured smooth muscle and endothelial cells is relatively consistent among a variety of injuries, and is manifest by alterations in the expression and response to cytokines (e.g., TGF-Beta, bFGF, IL-1 and endothelin), cytoskeletal constituents and protein synthesis. Physiologic consequences of vascular wall responses to injury may determine the mechanisms of delayed arterial narrowing observed in vasospasm. A series of experiments are proposed to address these hypotheses using two experimental paradigms for vasospasm developed in our laboratory. A simple and inexpensive rat femoral artery model enables chronic application of putative spasmogens or therapeutic agents to arterial wall for regulated periods of time. Parallel experiments in vitro utilizing smooth muscle and endothelial cell cultures allow quantitative assessment of phenotypic changes after exposure to hemoglobin or other substances. The models will be used to characterize the time course and calcium-dependence of contractile mechanisms in evolving vasospasm, to test the effectiveness of various therapeutic strategies (e.g. calcium antagonists, antioxidants) to inhibit arterial narrowing at different intervals, to examine the role and cellular mechanisms by which lipid peroxidation, inflammation and endothelin influence vasospasm, and to characterize alterations in content and distribution of cytoskeletal elements in endothelial and smooth muscle cells after exposure to blood.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL044458-05A1
Application #
2221496
Study Section
Neurology A Study Section (NEUA)
Project Start
1991-01-01
Project End
1999-05-31
Budget Start
1995-07-01
Budget End
1996-05-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Washington
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Ahn, Young Min; Gajdusek, Corinne; London, Susan et al. (2002) Sustained arterial narrowing after prolonged exposure to perivascular endothelin. Neurosurgery 50:843-8; discussion 848-9
Moon, C T; Gajdusek, C; London, S et al. (2001) Expression of endothelial nitric oxide synthase after exposure to perivascular blood. Neurosurgery 48:1328-32; discussion 1332-4
Luo, Z; Harada, T; London, S et al. (1995) Antioxidant and iron-chelating agents in cerebral vasospasm. Neurosurgery 37:1154-8;discussion 1158-9
Harada, T; Seto, M; Sasaki, Y et al. (1995) The time course of myosin light-chain phosphorylation in blood-induced vasospasm. Neurosurgery 36:1178-82;discussion 1182-3
London, S M; Mayberg, M R (1994) Kinetics of bromodeoxyuridine uptake by smooth muscle cells after arterial injury. J Vasc Res 31:247-55
Hadeishi, H; Mayberg, M R; Seto, M (1994) Local application of calcium antagonists inhibits intimal hyperplasia after arterial injury. Neurosurgery 34:114-21
Fuwa, I; Mayberg, M; Gadjusek, C et al. (1993) Enhanced secretion of endothelin by endothelial cells in response to hemoglobin. Neurol Med Chir (Tokyo) 33:739-43
Rostomily, R C; Mayberg, M R; Eskridge, J M et al. (1992) Resolution of petrous internal carotid artery stenosis after transluminal angioplasty. Case report. J Neurosurg 76:520-3