From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension

Abstract

SPECIAL MEDICAL EDITORIALSFrom bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertensionErnesto L. Schiffrin, and Rhian M. TouyzErnesto L. Schiffrin, and Rhian M. TouyzPublished Online:01 Aug 2004https://doi.org/10.1152/ajpheart.00262.2004MoreSectionsPDF (268 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations resistance arteries are vessels of ∼100–300 μm in lumen diameter that are an important site of resistance to blood flow. Small artery-dependent increased peripheral resistance may participate in development and complications of hypertension. The degree of remodeling of small arteries has prognostic significance over a 10-yr period, with worse prognosis for hypertensive subjects with greater remodeling. In almost all hypertensive subjects, a reduction in lumen and an increase in the media-to-lumen ratio are found, without increase in its media cross section, as a result of rearrangement of smooth muscle cells and increased collagen and fibronectin. Approximately 60% of hypertensive patients exhibit endothelial dysfunction already in stage 1 hypertension. Study of human vascular smooth muscle cells and of vessels from experimental animals has demonstrated that ANG II, aldosterone, and endothelin exert remodeling effects in large measure by activation of NADPH oxidase, and to lesser degree by stimulating xanthine oxidase and mitochondrial reactive oxygen species generation. Stimulation of angiotensin type 1 (AT1) receptors (AT1R) leads to increased reactive oxygen species in part via activation of nonreceptor tyrosine kinases such as c-src, and of PKC and phospholipase D, and thereby contributes to endothelial dysfunction by inactivating nitric oxide (NO). Treatment of hypertensive patients with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, but not β-blockers, corrects small artery structure and endothelial dysfunction, which may favorably affect outcome in the long term, beyond the 3–5 yr of randomized clinical trials during which most antihypertensives affect outcome similarly as long as blood pressure is well controlled.RESISTANCE ARTERIES IN HYPERTENSION: FROM CLINIC TO LABORATORYA major objective of translational research from bench to bedside is to test in humans novel therapeutic modalities developed through experimentation. However, because our understanding of many human diseases, such as hypertension, is still very limited, there is a critical need for bedside to bench research. We and other researchers have demonstrated that in human hypertension, resistance arteries undergo remodeling and altered reactivity. What remains uncertain, however, is how these processes occur and whether they are primary causative events or secondary adaptive phenomena. To answer some of these questions, it is imperative to extend bedside observations and findings to the bench, where molecular and cellular processes underlying vascular changes in hypertension can be studied in isolated vessels and cells in in vitro conditions. Ideally, one would like to examine cells directly involved in the pathological process under investigation. In hypertension, this includes vascular smooth muscle cells in resistance arteries. However, because of ethical and practical constraints, this is not always possible, and most studies investigating subcellular processes in hypertension are conducted, in large part, in cells from animal models, where hypertension is spontaneous or induced experimentally. When human cells are examined, they are usually derived from large arteries and veins obtained during surgery, from postmortem specimens, or from immortalized cell lines. Because these conditions do not control for blood pressure status and other variables of subjects from whom the cells are derived, it is inordinately difficult to extrapolate findings from such cell models to what may be happening in vascular cells during the development of hypertension. Because circulating blood cells are easily accessible from humans, many investigators have studied cellular events and signaling cascades in platelets, erythrocytes, and leukocytes as markers of events in vascular cells. However, this model is suboptimal because circulating cells are devoid of a supporting extracellular matrix and adventitia and have very different morphological and functional phenotypes compared with vascular smooth muscle cells.Over the past 10 yr, we successfully developed a system for the study of isolated vessels and vascular smooth muscle cells derived from human small arteries obtained from gluteal biopsies of subcutaneous tissue. This unique approach provides multiple benefits. First, small arteries and vascular cells derived from these are obtained from healthy individuals and well-characterized hypertensive patients, with or without treatment. Second, the vascular smooth muscle cells are derived from resistance arteries, which