Hypertension is an independent and potent risk factor for the development of atherosclerotic vascular disease. Despite the wealth of clinical and epidemiological data supporting this association, the precise molecular and cellular mechanisms have not yet been fully characterized. In this proposal, we will put forth the thesis that hypertension, like atherosclerosis is characterized by the development of a pro-inflammatory state in the arterial wall. The pro-inflammatory state is the result of humoral and mechanical stimuli that in turn induce the accumulation of macrophages in the arterial wall. In this proposal, we will utilize both in vivo and in vitro models to define the relationships between hypertension and vascular inflammation. The following Specific Aims are proposed:
Specific Aim I : Define the relationships between arterial wall stress and strain and vascular inflammation using osteopontin as a pro-inflammatory gene product.
Specific Aim II : To determine the molecular signaling mechanisms of mechanoregulation of osteopontin expression in vascular smooth muscle cells exposed to cyclic deformation.
Specific Aim III : To define the pro-inflammatory effects of hypertension in an animal model of atherosclerosis.
Specific Aim I V: To determine the functional significance of up-regulation of osteopontin expression on macrophage accumulation in hypertensive atherosclerotic animals.
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