It is well known that aged arterioles have increased constriction and the animals have an overall higher blood pressure. There have been several hypothesis that have arise as to the etiology of this process, with NO bioavailability being one of the most consistent issues in that the arterioles may make normal levels of NO via eNOS, but the ability to dilate has been severely diminished. The cause for this remains unknown. Recently we demonstrated that a potent NO scavenger, alpha globin, is uniquely expressed in endothelium of arterioles. Once more, preliminary data presented herein demonstrated an age-dependent increase in alpha globin that is consistent with movement of NO across the blood vessel wall. Because of this, we postulate that aged arterioles may develop increased alpha globin protein expression, providing a pathological ?sink? for NO, and decreasing the overall ability of these arterioles to dilate and increasing overall blood pressure. To accomplish this, we propose two aims:
Aim 1 we will determine changes in alpha globin protein expression and function in aged mice.
Aim 2 proposes that genetic deletion or modification of alpha globin could alter vascular reactivity and blood pressure in aged mice. This last aim uses the stable of mice generated by us to uniquely delete or over- express alpha globin specifically in the endothelium. Our exciting preliminary data demonstrates that alpha globin protein expression could be a key part of the vascular dysfunction observed in an aging vasculature. Our lab is unique in being able to tease the possible relationship between aging and alpha globin expression and function with the mice and reagents developed as part of the original R01.
Aging has a profound effect on the ability of blood vessels to constrict and dilate, which can alter blood pressure. In this application, we propose to test how a protein that can prevent blood vessel dilation, alpha globin, may be overexpressed in the vasculature of aging animals. We will use a host of genetically modified mice with alpha globin over- expression or deletion specific to the blood vessel to determine how this affects aged animals? ability to constrict or dilate, or regulate blood pressure.
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