The renin-angiotensin system in the vessel wall

The behavior of the circulating renin-angiotensin system is well known; however, the actions of renin and the generation of angiotensin (ANG) II at the tissue level are less appreciated. We have used rat models to study this issue. We examined the cleavage of human angiotensinogen to ANG I by human renin and its inhibition by a human renin inhibitor in an isolated perfused hindlimb preparation from rats which express the human angiotensinogen gene. With this model, we were able to show that renin acts at the site of the vascular wall, rather than in the lumen, to generate ANG I, which is subsequently converted to ANG II. Furthermore, the cleavage is specifically dependent on renin and not on other lysosomal proteases. The renin gene is present in the vascular wall; however, whether or not renin is generated locally to act locally, or whether renin is taken up from the circulation to act locally was not clear. We used the same strain of transgenic rats to test this issue and showed that renin can be taken up by cardiac or coronary vasculature tissue and induces long-lasting local ANG II generation. Locally formed ANG I was converted to ANG II more effectively than infused ANG I. We did additional studies to examine the conversion step from ANG I to ANG II in the vessel wall. We perfused hindlimbs from Sprague-Dawley rats with ANG I and observed ANG II production, which was linear over a 10,000-fold concentration range of ANG I. However, when we increased angiotensin converting enzyme (ACE) gene expression in the vascular bed, which also increased ACE tissue concentrations, we were nevertheless able to demonstrate increased ANG II production with ACE upregulation. Taken together, these results demonstrate (1) the cleavage of local angiotensinogen to ANG I within the vascular wall by renin, (2) renin uptake from the circulation to evoke that local effect, and (3) a potential regulatory effect by vascular tissue ACE on ANG II production in the vessel wall. The findings support the notion of localized renin-angiotensin system-related effects on vascular function and structure.