Abstract 495: Mouse Model of Mesenteric Ischemia Secondary to Vascular Calcification and Atherosclerosis

Objective: Atherosclerosis is a leading cause of chronic mesenteric ischemia (CMI), defined as intestinal hypoperfusion resulting from stenosis of mesenteric arteries. Symptoms of CMI range from non-specific abdominal pain and weight loss to aversion of food resulting in cachexia. In this study we aim to define intestinal ischemia and its effects on gastrointestinal structure and function in an in vivo model of atherosclerosis. Hypothesis: Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) under conditions of hypercholesterolemia in a mouse model will lead to atherosclerosis causing intestinal ischemia. Methods and Results: We have previously established that endothelial TNAP overexpression (eTNAP) results in calcification of medium-sized arteries including mesenteric. In this study eTNAP was combined with a point mutation in the low-density lipoprotein receptor ( ldlr ^WHC). When fed an atherogenic diet (Paigen’s diet, starting at 8 weeks of age), WHC-eTNAP mice developed acute body weight loss (>15% from baseline), whereas WHC mice continued to gain weight. Examination of the mesenteries of WHC-eTNAP demonstrated eccentric vascular remodeling and stiffening, as well as calcification of atherosclerotic plaques (n=4). Mesenteric arteries of WHC were not affected (n=3). WHC-eTNAP (n=2) mice developed extensive atherosclerosis of submucosal arterioles in the colon where most vessels were narrowed or occluded. Examination of the small intestine in WHC-eTNAP mice showed structurally distressed villi accompanied with an increase in goblet cells and fragmentation of the epithelial layer possibly reflecting cell death. The colon demonstrated loss of goblet cells and signs of denuding of the epithelium. Conclusion: Atherosclerosis induced by overexpression of TNAP causes occlusion of mesenteric arteries as well as structural pathology in the small and large intestine