The overall aim of this proposal is to test the hypothesis that, in fowl, elevation of blood pressure (BP) and changes in local hemodynamic forces causally induce dysfunction of endothelium-vascular smooth muscle (VSM) communication that activates local humoral factors resulting in VSM modulation from contractile to synthetic phenotypes. A long-term goal is to elucidate the cellular mechanism of neointimal lesions and its relation to atherosclerosis. The unique aspects of the avian vascular model include: 1) fowl show age- (sex-) dependent high BP and high circulating catecholamines. 2) Neointimal plaques that resemble those formed by a balloon catheter-induced endothelium injury develop spontaneously at early ages, most frequently in the distal segment of the abdominal aorta (lesion- prone area), without feeding the fowl excess fat or cholesterol. 3) Fowl VSM cells are heterogenous, and one type may be atherogenic.
AIM I is to determine whether the magnitude (and velocity) of the pulse pressure wave are greater in the lesion-prone area and whether they further increase as BP and plasma catecholamines become higher. Changes in pulse pressure wave amplitude/velocity along the decending aorta and plasma catecholamines will be measured in chicks, pullets, and mature chickens.
AIM II is to determine whether maturation/age-dependent modulation in VSM phenotypes shows a causal relationship with elevated BP and/or circulating catecholamines. BP will be lowered by 1) mechanical constriction of the aorta, 2) beta-adrenoceptor blocker, and 3) 6-hydroxydopamine plus reserpine.
AIM III is to elucidate whether inhibition of PDGF, blockade of alpha beta integrins, or treatment with nitric oxide donor prevents VSM phenotypic modulation and neointima formation in vivo. The drugs will be locally or systemically applied.
For AIMS II and III, representative phenotypic modulations in morphology, cytoskeletal protein, extracellular matrix, nitric oxide synthase, and function will be determined. The novel information forthcoming will elucidate, first, whether sustained elevation of BP causally induces VSM phenotypic modulation/neointima; second, whether local hemodynamic and humoral factors trigger phenotypic modulation in vivo; and, third, whether phenotypic modulation of VSM precedes the development of neointimal plaques. Furthermore, the outcome derived from the proposed studies will help integrate available cellular and molecular information into intact animal levels and help us understand the mechanism of vascular remodeling and atherosclerosis in humans and other mammals. Drs. M. Kiani (analysis of hemodynamic forces), L. C. Gerstenfeld (osteopontin molecular biology), R. F. Wideman (poultry physiology, nutrition), and D. B. Thomason (muscle molecular biology) will provide consultation.
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