The effects of type-2 diabetes on cerebrovascular structure and function
Harris, Alex Keith
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Background: Cardiovascular disease, including stroke, is the leading cause of death in diabetes. Endothelin (ET-1) is upregulated in diabetes and previous studies have suggested that ET-1 may be involved in vascular remodeling and dysfunction in peripheral vessels. However, the effects of diabetes and ET-1 on the cerebrovasculature remained unknown. The central hypothesis of these studies was that: 1) cerebrovascular remodeling, characterized by ECM deposition and/or rearrangement, occurs in diabetes 2) ET-1 contributes to this process by altering the expression and activity of MMPs 3) diabetes induces vascular dysfunction in the form of either impaired relaxation or exacerbated contractile responses to vasoconstrictors. The rationale was that an understanding of the effects of diabetes on the cerebrovasculature would facilitate the design of future studies aimed at prevention of cerebrovascular disease in diabetes. Methods and Results: Control Wistar and diabetic Goto-Kakizaki (GK) rats, either untreated or subjected to 4 weeks of ETA or ETB receptor antagonism, were sacrificed at 18 weeks of age and vascular structure and function were assessed in middle cerebral arteries (MCA) and basilar arteries respectively. GKs exhibited remodeling of MCAs which was associated with elevated ET-1 levels and dysregulation of MMPs. In addition, basilar arteries from GKs were hyperreactive to ET-1 and had impaired endothelium dependent relaxation. ETA receptor antagonism restored MMP activity and decreased wall:lumen ratio in MCAs while decreasing ET-1 sensitivity and restoring ACh induced relaxation of basilar arteries. ETB receptor blockade significantly reduced medial thickening in MCAs and decreased basilar ET-1 sensitivity. Discussion: Vascular structural changes influence function by altering distensibility, elasticity, and compliance of blood vessels. In addition, disruption or modification of the extracellular matrix can uncover cryptic signals which in turn can begin a signal cascade leading to further cell proliferation and migration. These data suggest that Type-2 diabetes, devoid of confounding conditions such as hypertension and hyperlipidemia, induces structural as well as functional changes in the cerebrovasculature which are at least modulated, if not regulated by the endothelin system. In addition, the similarity of results obtained with ETA/ ETB blockade indicate a greater involvement of ETB receptors in the development of diabetic vasculopathies.