Microvascular injury, without denudation of endothelium is produced with two different techniques (1) a light/dye technique employing a mercury lamp and intravascular sodium fluorescein (2) a He-Ne laser in the presence of Evan's blue. Even without endothelial denudation the endothelial injury produces local platelet aggregation and alters the tone (diameter) of the injured microvessels. The endothelial injury also changes the normal dilating action of acetylcholine to a constriction. The latter suggests interference with an endothelial dependent relaxing factor (EDRF) and demonstrates the probable existence of such a factor in brain microvessels. The effects just described are monitored in pial vessels of mice using intravital microscopy. The mechanisms responsible for the local platelet aggregation and the altered tone will be investigated using pharmacologic probes interacting with the following: cyclooxygenase-prostaglandin-thromboxane pathway, with prostacyclin, with lipoxygenase, with calcium channels. We will attempt to mimic responses to injury by using agents producing radicals or thromboxane. We also will couple the demonstration of endothelium dependent relaxing factor(s) in the microcirculation, with an analysis of the nature of the factor(s) through the use of pharmacologic probes. Finally, in our analysis of factors interferring with platelet aggregation in response to endothelial injury, we will separately study platelet aggregation in vitro, and vessel walls using electromicroscopy. These latter studies will begin to determine whether drugs that affect the response of platelets in vivo, are actually working on the platelet or whether they are, instead or also, altering the amount of injury at the vessel wall. The proposed studies are relevant to important clinical problems such as (1) cerebral infarction due to small vessel obstruction following endothelial damage (2) hypertrophy of arteriolar walls which might be dependent upon release of smooth muscle mitogens during enhanced platelet aggregation (reported by some to occur in hypertension) (3) altered vascular reactivity following endothelial injury in such diverse conditions as ischemia, hypertension, vascular rupture with subarachnoid hemorrhage, trauma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035935-04
Application #
3350401
Study Section
(SRC)
Project Start
1985-09-30
Project End
1990-09-29
Budget Start
1988-09-30
Budget End
1989-09-29
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Rosenblum, W I (1997) Tetrahydrobiopterin, a cofactor for nitric oxide synthase, produces endothelium-dependent dilation of mouse pial arterioles. Stroke 28:186-9
Rosenblum, W I (1997) Selective impairment of response to acetylcholine after ischemia/reperfusion in mice. Stroke 28:448-51; discussion 451-2
Rosenblum, W I; Nelson, G H (1996) Singlet oxygen scavengers affect laser-dye impairment of endothelium-dependent responses of brain arterioles. Am J Physiol 270:H1258-63
Rosenblum, W I (1996) Conservation of flow demonstrated using the two-slit velocimeter and cross correlator in epiilluminated surface microvessels of the mouse brain. Microcirculation 3:187-90
Rosenblum, W I; Murata, S (1996) Antisense evidence for two functionally active forms of nitric oxide synthase in brain microvascular endothelium. Biochem Biophys Res Commun 224:535-43
Rosenblum, W I; Nelson, G H; Bei, R A et al. (1996) Vitamin E ameliorates adverse effects of endothelial injury in brain arterioles. Am J Physiol 271:H637-42
Rosenblum, W I; Nelson, G H; Wormley, B et al. (1996) Role of platelet-endothelial cell adhesion molecule (PECAM) in platelet adhesion/aggregation over injured but not denuded endothelium in vivo and ex vivo. Stroke 27:709-11
Rosenblum, W I; Wormley, B (1995) Selective depression of endothelium-dependent dilations during cerebral ischemia. Stroke 26:1877-81;discussion 1882
Rosenblum, W I; Nelson, G H; Murata, S (1995) Protein synthesis and rapid recovery of endothelium-dependent dilation after endothelial injury of pial arterioles. Am J Physiol 268:H512-5
Murata, S; Rosenblum, W I; Shimizu, T et al. (1995) Delayed platelet adhesion/aggregation at sites of endothelial injury in mouse cerebral arterioles after transient elevations of blood pressure and shear. Stroke 26:650-3;discussion 654

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