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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105299-03
Application #
8293205
Study Section
Special Emphasis Panel (ZHL1-CSR-W (S1))
Program Officer
OH, Youngsuk
Project Start
2010-09-30
Project End
2014-06-30
Budget Start
2012-07-30
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$392,105
Indirect Cost
$144,605
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Wang, Dong; Deuse, Tobias; Stubbendorff, Mandy et al. (2015) Local MicroRNA Modulation Using a Novel Anti-miR-21-Eluting Stent Effectively Prevents Experimental In-Stent Restenosis. Arterioscler Thromb Vasc Biol 35:1945-53
Raaz, Uwe; Schellinger, Isabel N; Chernogubova, Ekaterina et al. (2015) Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus. Circ Res 117:513-24
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Raaz, Uwe; Zöllner, Alexander M; Schellinger, Isabel N et al. (2015) Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development. Circulation 131:1783-95
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Maegdefessel, Lars; Spin, Joshua M; Tsao, Philip S (2014) New ways to dismantle a ticking time bomb: microRNA 712/205 and abdominal aortic aneurysm development. Arterioscler Thromb Vasc Biol 34:1339-40
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Spin, Joshua M; Tsao, Philip S (2014) Battle of the bulge: miR-195 versus miR-29b in aortic aneurysm. Circ Res 115:812-3
Deuse, Tobias; Hua, Xiaoqin; Wang, Dong et al. (2014) Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature 509:641-4