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

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Abstract
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. A 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 contribute to blood pressure regulation, elevation of peripheral resistance and development of hypertension. Third, low-passaged cells that maintain their morphological and functional properties are studied. With the use of this approach, implementing “bedside to bench” research is realized, gaining a fuller understanding of cellular processes and signaling pathways contributing to vascular remodeling in hypertension. Our long-term goal is to identify putative genes and/or proteins fundamentally involved in hypertensive vascular pathology that could be used as targets for manipulation in the prevention and management of human hypertension. Ultimately and ideally, our findings will echo back from “bench to bedside” to test novel therapeutic strategies developed through experimentation. We will recapitulate our own scientific itinerary from the bedside and studies of human small artery remodeling to the bench and the use of cells derived from these human small arteries as well as cells from vessels from experimental animals, and with the insights gained in the latter, back to the bedside, with studies of the action of agents that block these mechanisms, in particular the inhibitors of the renin-angiotensin system, and their effect on vascular remodeling in hypertensive humans. Increased peripheral resistance is the hallmark of essential hypertension ([94][1]) ([Fig. 1][2]). Increased...

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