The overall aim of this proposal is to test, using a unique avian naturally occurring high blood pressure (BP) model, a causal relationship among incremental increases in BP, hemodynamic forces selective to the lower segment of the abdominal aorta and endothelial dysfunction, leading to the formation of neointimal plaques (NPs). A long-term goal is to elucidate the specific hemodynamic forces and molecular mechanisms that determine the heterogeneity of atherosclerosis-prone regions between genders and among species. We found that incremental increases in BP during maturation of chicks, but not plateau levels of BP, are causally related to NP formation and medial thickening in the lower part of the abdominal aorta above the bifurcation (NP-prone area); this can be prevented by antihypertensive treatment or by oral L-arginine (Arg) supplement. Pulse wave velocity (PWV) measured in the descending aorta, an index for arterial wall stiffness, becomes progressively higher with maturation in male chicks, whereas in females, PWV was restored to lower levels after sexual maturation.
AIM I is to elucidate hemodynamic and molecular factors selective for NP-prone regions by examining whether 1) preventing the rise in BP prevents the elevation of PWV, 2) hardened vascular walls are more susceptible to further injury, 3) gender-dependent increases in PWV may partly depend on gonadial hormones; and 4) shortening of telomere length in the lesion-prone area occurs inversely to the rise in BP.
AIM II is to determine whether 1) endothelial dysfunction occurs (increased superoxide anion, SOA, and peroxynitrite) prior to NP formation, whereas endothelial nitric oxide synthase is relatively well maintained, in the NP-prone area; and 2) L-Arg supplement initially prevents, but later aggravates, vascular lesions in injured aorta.
AIM III is to elucidate whether Ang II exerts a dual action in fowl aorta: whether, in intact vascular walls, Ang II helps maintain vascular wall integrity via an endothelial mechanism, whereas in injured walls, it stimulates fibroblast growth/mobilization in adventitia. We will examine the involvement of endothelium-dependent hyperpolarization factor (EDHF)/K* channels in Ang II-induced endothelial mechanism and 2) the role of Ang II, via adventitial receptors, in vascular growth (during development) and NP formation (injured aorta). Novel aspects of the proposed studies and outcome include: 1) characterization of hemodynamic forces and cellular/molecular mechanisms selective to the NP-prone area, gender, and age; 2) elucidation of the roles of unbalanced NO and SOA levels in NP formation; and 3) elucidation of the role of the adventitial Ang II receptors in NP formation. The proposed projects will be supported by five distinguished consultants. ? ?
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