SPECIAL ARTICLE www.jasn.org Frontiers in Nephrology: Early Atherosclerosis—A View Beyond the Lumen Mario Gossl,* Lilach O. Lerman,† and Amir Lerman* Divisions of *Cardiovascular Diseases and †Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota ABSTRACT permeability) of the endothelium, even- Endothelial dysfunction is an established clinical marker of early coronary artery tually leads to formation of histologically disease and has been shown to be associated with increased cardiovascular mor- identifiable atherosclerotic lesions. At bidity and mortality. New concepts now extend the view of endothelial dysfunction this point, atherogenesis may become a beyond the traditional involvement of the coronary arterial endothelium alone. self-perpetuating process, a vicious cycle Recent research indicates that the coronary vessel wall, especially the vasa vaso- in which accumulating inflammatory rum, as well as bone marrow–derived endothelial progenitor cells may be subject and noninflammatory cells release che- to proatherosclerotic changes, even before the development of angiographically mokines, cytokines, and growth and evident endothelial dysfunction; therefore, “microvascular endothelial dysfunction,” transcription factors that attract more which is composed of dysfunction of the vasa vasorum’s endothelium as well as inflammatory cells and lead to progres- “microcellular endothelial dysfunction,” reflecting impaired mobilization and func- sion of the atherosclerotic lesion and tion of endothelial progenitor cells, may precede “macrovascular endothelial dys- eventually to local complications, function.” Vasa vasorum neovascularization, with endothelial leakage and dysfunc- namely plaque rupture with local arterial tion increasing influx of proinflammatory and proatherogenic cellular and thrombosis (Figure 1). noncellular substances into the vessel wall, is proposed as one feature of this new Recent research has broadened our concept. In addition, the role of bone marrow–derived endothelial progenitor cells view of the atherosclerotic process. is discussed as are the potential impact of impaired progenitor cell mobilization, Whereas the luminal endothelium was tra- release from the marrow, and function in acute and stable coronary artery disease. ditionally considered as playing the main Finally, potential future therapies are proposed, focusing on interventions that may role in vascular regulations, we know today prevent or diminish the development of the microvascular and microcellular endo- that a considerable amount of endothe- thelial dysfunction. lium is also present in the abluminal part of the vessel wall, at the level of the vasa vaso- J Am Soc Nephrol 18: 2836–2842, 2007. doi: 10.1681/ASN.2007030333 rum. Several studies2–5 identified a possible major impact of inflammatory invasion from the adventitia into the inner vessel THE TRADITIONAL VIEW OF merous studies have identified risk fac- wall layers, rather than only the entrance ATHEROSCLEROSIS tors for the development of endothelial via the luminal endothelium. dysfunction, but factors such as hyper- It is therefore obvious that the vascu- Atherosclerosis is considered a systemic, cholesterolemia, smoking, diabetes, met- lar endothelium and its interaction with chronic inflammatory disease predomi- abolic syndrome, and hypertension are the surrounding environment play a cru- nantly of the arterial vessel wall with local the most prominent. cial role in the pathogenesis of athero- complications that determine morbidity Endothelial dysfunction involves the and mortality. The classic response-to- trans-formation of vasoprotective prop- injury model described physical injury to erties of the endothelium into proath- Published online ahead of print. Publication date the endothelium as the first step of erosclerotic features: The endothelium available at www.jasn.org. atherogenesis, but it has been subse- becomes procoagulant, produces vaso- Correspondence to: Dr. Amir Lerman, Division of quently recognized that endothelial dys- constrictive molecules, and releases cyto- Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN function (e.g., the impaired bioavailabil- kines that attract inflammatory cells, in- 55905. Phone: 507-255-6670; Fax: 507-255-1824; ity of the endothelial-derived vasodilator cluding lymphocytes and macrophages. E-mail: [email protected] substance nitric oxide [NO]) may also be Accumulation of these inflammatory Copyright © 2007 by the American Society of considered as a functional “injury.”1 Nu- cells, as well as increased leakiness (i.e., Nephrology 2836 ISSN : 1046-6673/1811-2836 J Am Soc Nephrol 18: 2836–2842, 2007 www.jasn.org SPECIAL ARTICLE sclerosis. Exposed to multiple circulating adequate interaction is crucial for a suc- important role in the repair of injured en- atherogenic risk factors, it undergoes a cessful repair. Endothelial dysfunction has dothelium, and EPC dysfunction may be a constant injury-and-repair process that been identified as a marker of early athero- very early marker of atherosclerotic may result in several potential outcomes, sclerotic disease before the development of disease. which may also be a progressive cascade a lumen-compromising plaque and, The pathomechanisms of conduit ves- of events (Figure 1): hence, as an indicator of the unsuccessful sel endothelial dysfunction have been rela- repair process. As a result, endothelial dys- tively well established.8 Therefore, in this 1. The repair is successful and heals the endothelium function has been shown to be associated review, we focus on possible expression and vascular wall, and endothelial function remains 6 normal. with adverse cardiovascular outcomes ; and consequences of endothelial dysfunc- 2. The repair is unsuccessful, and although the endo- however, endothelial dysfunction not only tion within the vessel wall and EPC, two thelium and vascular wall show no morphologic may be the result of unsuccessful repair but novel and exciting areas of current basic changes, endothelial dysfunction occurs (impaired also may actually be among the underlying and clinical research that may open new bioavailability of NO, abnormal vasoconstriction). causes. Indeed, Lerman and Zeiher7 re- ways for therapeutic approaches. 3. The repair is unsuccessful, results in vascular scar- ring characterized by fibrotic tissue and calcifica- cently suggested that the site of endothelial tion, and promotes the injury process. dysfunction should be extended beyond MICROVASCULAR ENDOTHELIAL 4. The repair is lacking or insufficient, and the injury the traditional location at the conduit ves- DYSFUNCTION OF THE VASA process continues into complicated atherosclerotic sels into the vessel wall and possibly even VASORUM lesions. into the bone marrow, the origin of endo- The proper function of all systems in- thelial progenitor cells (EPC). In addition, Early endothelial injury (e.g., in hyper- volved in the repair process as well as their EPC have been demonstrated to play an cholesterolemia, smoking, or diabetes) Figure 1. Four different outcomes of the repair process in early atherosclerosis, focusing on two participating systems reviewed here: Vasa vasorum and bone marrow–derived EPC. The initial event is an injury inflicted on the endothelial layer through genetic disposition and/or atherosclerotic risk factors, both at the luminal side and at the level of vasa vasorum within the vessel wall. Subsequently, endothelial cell activation, vasa vasorum neovascularization, and mobilization of EPC take place. (1) Normal, successful repair of the injury, resulting in a preserved endothelial function and vessel wall morphology. (2 through 4) Results of abnormal, unsuccessful repair: (2) The vessel wall still shows no morphologic changes, but endothelial function is impaired. (3) The vessel wall morphology changes into vascular scarring characterized by fibrotic tissue and calcification. (4) The repair is lacking or insufficient, injury continues, and a complicated atherosclerotic lesion develops. J Am Soc Nephrol 18: 2836–2842, 2007 Endothelial Dysfunction: A New View 2837 SPECIAL ARTICLE www.jasn.org may lead to a leaky endothelial layer.9 substances (e.g., oxidized LDL, cyto- hypercholesterolemia is associated not This early injury not only takes place at kines, macrophages) into the vessel only with macrovascular endothelial the luminal endothelium but also may wall12,13 and that they in turn also play a dysfunction (i.e., paradoxic vasocon- conceivably extend to the endothelium significant role in draining the arterial striction) but also with dysfunction of of the vasa vasorum within the vessel vessel wall.14 Moreover, it has been the vasa vasorum’s endothelium. This wall. Vasa vasorum (both arterial and ve- shown in a porcine model of hypercho- may lead to intermittent vasoconstric- nous) are microvessels located within the lesterolemic early atherosclerosis that tion causing hypoxia within the vessel wall of bigger arteries, such as the renal vasa vasorum neovascularization occurs wall and subsequent reactive, local pro- and coronary arteries, providing blood before the development of atheroscle- duction of vascular endothelial growth supply to and drainage from the vessel rotic plaques.15–17 This vasa vasorum factor (VEGF) with enhanced vasa vaso- wall.10 Importantly, the arterial vasa va- neovascularization leads to an average rum neovascularization and a further in- sorum originate either from the artery it- increase