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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:287.)
© 2006 American Heart Association, Inc.

Vascular Biology

Radiation Induces Endothelial Dysfunction in Murine Intestinal Arterioles via Enhanced Production of Reactive Oxygen Species

Ossama A. Hatoum; Mary F. Otterson; Doron Kopelman; Hiroto Miura; Igor Sukhotnik; Brandon T. Larsen; Rebecca M. Selle; John E. Moulder; David D. Gutterman

From the Division of Cardiovascular Medicine (O.A.H., H.M., B.T.L., R.M.S., D.D.G.), Department of Surgery (M.F.O., D.K., I.S.), and Department of Radiation Oncology (J.E.M.), Froedtert Memorial Lutheran Hospital, VA Medical Center, Medical College of Wisconsin, Milwaukee.

Correspondence to Ossama A. Hatoum, MD, MS, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226. E-mail ohatoum{at}mcw.edu

Objective— Endothelial dysfunction and vascular dysregulation contribute to the pathological effects of radiation on tissues. The objectives of this study were to assess the acute effect of irradiation on acetylcholine (Ach)-induced dilation of gut submucosal microvessels.

Methods and Results— Rats were exposed in vivo to 1 to 9 cGy in 3 fractions per week on alternate days for 3 successive weeks for a total dose of up to 2250 cGy. Submucosal microvessels were isolated after varying levels of irradiation. Diameters of isolated vessels were measured using videomicroscopy, and the dose-response relationship to Ach was determined. Dihydroethidine and 2', 7'-dichlorodihydrofluorescein diacetate fluorescent probes were used to assess reactive oxygen species (ROS) production. After constriction (30% to 50%) with endothelin, dilation to graded doses of Ach (10^–9–10^–4 M) was observed in control vessels (maximal dilation [MD] 87±3%; n=7). However, Ach-induced dilation was reduced in vessels from irradiated rats (MD=3±9%; n=7; P=<0.05 versus controls). Significant increases in superoxide and peroxides were observed in irradiated microvessels. Irradiated microvessels pretreated with superoxide dismutase–mimetic demonstrated significant improvement in Ach-induced vasodilation compared with irradiation alone, suggesting that superoxide contributes to impaired dilation to Ach after irradiation.

Conclusions— Radiation induces acute microvascular dysfunction in the resistance arterioles of the intestine. Enhanced ROS contribute to this dysfunction and therefore may represent a novel therapeutic target to minimize radiation toxicity in the gut.

In irradiated gut from rats, a profound microvascular endothelial dysfunction was demonstrated. Excess levels of superoxide and peroxides were found to play a key role in this endothelial dysfunction. Defining the mechanisms that underlie microvascular dysfunction after radiated tissue should yield important insight into the pathogenesis of radiation-induced gastrointestinal complications.

Key Words: radiation • endothelial dysfunction • microvessels • dihydroethidine • 2', 7'-dichlorodihydrofluorescein diacetate

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