Sublethal copper deficiency during developmental periods induces cerebral aneurysms

Abstract

background: Noninvasive pharmacological therapy options are extremely necessary for cerebral aneurysms. To identify the pathophysiological target, we developed an optimal model to review human intracranial aneurysms (IAs). Methods: Rats were fed copper-free, low-copper, normal, or copper-rich diets at different time periods from gestation to adulthood. The incidences of IAs were evaluated and autopsies were performed to determine the coexistence of cardiovascular diseases. Results: While rats fed a copper-free diet from gestation were associated with high mortality rates (~80%) resulting from ascending aorta aneurysm rupture, a low-copper diet model led to acceptable mortality rates (~18%) and produced IAs and subarachnoid hemorrhage in about 45% and 9%, respectively. Delayed copper supplementation in the rats primed for copper deficiency from gestation failed to decrease the development of aneurysms. Higher proportion of IAs up to 90% in the rats fed with low-copper diet from gestation period can be easily achieved by flow-augmentation by common carotid artery occlusion and/or hypertension induction with deoxycorticosterone acetate. In addition, we proposed genes involving extracellular matrix and vascular remodeling and some miRNAs as effectors of aneurysm development using this model. Conclusion: We propose a simple and relevant model of the human IAs by a simple measure to decrease the activity of lysyl oxidases by dietary copper deficiency from gestation. A highly efficacious method to create IAs without any direct manipulation of intracranial arteries would be a powerful tool for future aneurysm studies.