Local synthesis of vasoactive peptides, e.g. angiotensin, may be one of several mechanisms by which vascular endothelium participate in the control of vascular function. Multiple lines of evidence support the existence of a vascular wall renin-angiotensin system (RAS) which is independent of the circulating system. Immunohistochemical and biochemical studies have demonstrated that components of the renin-angiotensin system exist in blood vessel walls especially in the intima. Using cultured bovine aortic endothelial cells (BAEC), we documented intracellular renin-angiotensin expression (Circ. Res. 58:312, 1985). More recently, using monoclonal antibodies to human renin, we detected immunoreactive renin in cultured human iliac artery endothelial cell, by both direct radioimmunoassay and immunocytochemistry. Using HPLC and radioimmunoassay, we have been able to demonstrate angiotensins both intracellularly in BAEC and in the culture media where the peptides accumulate in a time-dependent manner. We have been unable to detect renin or angiotensinogen in the media. Taken together, our data suggest that cultured aortic endothelial cells contain the renin-angiotensin system and that the renin-angiotensinogen reaction occurs principally inside the cells. Angiotensin is then secreted extracellularly where it may exert its action. We propose to carry out an in-depth study on the biology of the endothelial renin-angiotensin pathway. Issues to be studied are: (1) the biochemical characterization and the subcellular localization of the various components of this intracellular renin-angiotensin system, (2) the regulation of this local system, especially the regulation of angiotensin secretion, and (3) the identification of the function(s) of endothelial renin-angiotensin system. We postulate that endothelial production of angiotensins is locally regulated and these peptides may exert autocrine or paracrine influences on the blood vessel wall, thereby affecting local vascular tone. By elucidating the cellular mechanisms of angiotensin synthesis and secretion as well as the factors which regulate these processes, we should improve our understanding of the biology of this fundamental cardiovascular regulatory system.
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