The overall aim of this proposal is to investigate the role of the VES unit in the control of vascular function, utilizing a unique interaction between ANG and the avian vascular cells. A long-term goal will be to elucidate the cellular and molecular mechanisms of the VES communication and to determine local humoral and hemodynamic factors that regulate the VES unit in normal and impaired blood vessels. The unique aspects of the avian vascular model include: 1) Birds have elevated blood pressure and plasma cateholamines and show both spontaneously developed and endothelium injury- induced vascular neointimal plaques. 2) Two types of vascular smooth muscle (VSM) cells appear to be present, one of which may be atherogenic. 3) ANG exerts endothelium-dependent vasorelaxation via endothelium-derived relaxing factor (EDRF)/cGMP and vasopressor action by releasing catecholamines; these actions are selectively inhibitable. 4) Prostacyclin synthase appears absent in fowl aortae. The applicant hypothesizes that endothelial dysfunction, due to damage caused by high perfusion pressure, and impaired VES communication may lead to, or aggravate, neointimal proliferative lesions in atherogenesis- prone vessels. The dual interaction of ANG with vascular cells in fowl will provide a useful tool for studying the role of the VES unit in the regulation of normal and impaired vascular function.
Aim one is to characterize age- (or blood pressure-) related phenotype changes of the VES unit of fowl aortae focusing on: 1) endothelial function (endothelium-dependent relaxation and permeability) and cellular signals (cGMP/nitric oxide) and 2) VSM function (contraction and growth promotion) and calcium signalling and their relationship to blood pressure and neointimal proliferative plaques. Four age-groups will be used, representing those preceding and following establishment of vascular lesions and blood pressure. Furthermore, morphological and physiological properties will be compared between naturally developed and endothelium injury-induced neointimal plaque cells.
Aim two is to determine whether stimulation of endothelial function by ANG or inhibition of alpha-adrenergic receptors helps maintain normal VES unit function and prevents development of vascular plaques and whether, in contrast, endothelial impairment (by EDRF/nitric oxide synthase inhibition or endothelium injury) or increased catecholamines accelerate VES unit dysfunction and neointimal hyperplasia, possibly leading to elevation of blood pressure. ANG and inhibitors will be infused by osmotic minipump, and the morphology and function of the VES unit will be examined as above. ANG interaction with the vascular system in fowl will provide an unique model for studying the role and cellular mechanism of the VES unit in the control of normal and impaired vascular function.
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