Aortic thromboxane receptor deficiency alters vascular reactivity in cholesterol-fed rabbits

Abstract

Hypercholesterolemia is considered a major risk factor in the development of atherosclerotic disease. The endothelium is the source of a number of vasoactive compounds which may be altered by the disease process. For example, synthesis of the arachidonic acid metabolite thromboxane A 2 (TXA 2) increases in atherosclerosis. Non-selective blockade of vascular and platelet thromboxane (TP) receptors retards the progression of the disease in various animal models. We have previously identified a subset of NZW rabbits that lack only vascular (v) TP receptors, referred to as vTP−. These rabbits provide a unique model to elucidate the role of vascular TP receptors in hypercholesterolemia. Studies evaluated vascular responses to phenylephrine and acetylcholine in isolated aortic rings obtained from vTP− and vTP+ rabbits fed 0.5% cholesterol diet for a period of only 3 weeks. In the cholesterol-fed vTP− rabbits, contractions to phenylephrine were reduced compared to the vTP+ cholesterol-fed rabbits. Acetylcholine-induced relaxations were greater in cholesterol-fed vTP− rabbits compared to cholesterol-fed vTP+ rabbits. While the overall incidence of aortic lesions was small after only 3 weeks of cholesterol-feeding, results indicated a reduction in lesions in the vTP− compared to the vTP+ rabbits. In summary, these studies are the first to show that if rabbits lack only vascular TP receptors, impaired vascular reactivity responses normally associated with hypercholesterolemia are diminished.