Longitudinal studies indicate that arterial stiffness can predict incident hypertension but a causal relationship has yet to be demonstrated. We have demonstrated in a rodent model of insulin resistance that aortic stiffness occurs at an early age before the development of hypertension. In addition, we have documented increased expression of the matrix-regulatory and osteogenic transcription factor, core binding factor alpha1 (Cbfa1) in the aortic wall. We hypothesize that the insulin resistant milieu results in inappropriate expression of Cbfa1 in vascular tissue, leading to transcription of a panel of genes associated with vascular fibrosis and aortic stiffness.
In Specific Aim 1, we will use both genetic and diet-induced models of insulin resistance/hyperinsulinemia to determine effects upon Cbfa1 expression and activity. Thiazolidinedione treatment will be used to enhance insulin sensitivity while pharmacological agents to modulate angiotensin and nitric oxide activity signaling will be used to elucidate the effects upon aortic Cbfa1 expression.
In Specific Aim 2, we will explore further the relationship between Cbfa1 and vascular stiffness using a novel vascular smooth muscle-specific Cbfa1 transgenic mouse. Aortic gene expression and smooth muscle cell growth patterns will be correlated to ex vivo measures of material stiffness. In addition, we will produce a new mouse model that expresses a dominant-negative Cbfa1 in vascular smooth muscle and test the essential role of Cbfa1 in insulin resistance-induced vascular stiffness. Finally, in Specific Aim 3, we will determine the effects of Cbfa1 overexpression on arterial stiffness in vivo and on development of hypertension. Pharmacological and genetic manipulations of Cbfa1 activity will be tested for subsequent effects upon vascular stiffness and blood pressure.
These specific aims will investigate a novel mechanism that may underlie vascular stiffness in the setting of insulin resistance. Moreover, this model will give us the opportunity to determine the temporal relationship of arterial stiffness and elevations in blood pressure. Finally, direct inhibition of Cbfa1 activity will test whether targeting vascular stiffness will have benefit in inhibiting development of hypertension.
We have observed increased levels of Cbfa1, a gene related to extracellular matrix and calcification, in the aorta of animal models of vascular stiffness. We propose to use a combination of material testing and imaging modalities to clarify the underlying mechanisms of how this gene can regulate vascular stiffness as well as predispose to the development of hypertension.
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