Early Atherosclerosis—A View Beyond the Lumen

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 scarring 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 of endothelial exchange surface crease in endothelial exchange surface, self (vasa vasorum interna) or from its within the vessel wall of Ͼ60%,11 which creating a vicious cycle. major branches (vasa vasorum externa) conceivably further promotes influx of Together, these important facts sug- and are thus directly connected to the proatherogenic substances into the ves- gest that the inner and the outer arterial systemic circulation (Figure 2). The sig- sel wall. In addition, using cryogenic mi- vessel wall layers are simultaneously ex- nificance of the vasa vasorum becomes crocomputed tomography, we demon- posed to proatherosclerotic cellular and evident when considering the endothe- strated that the drainage function of noncellular blood components. In fact, lial exchange surface that they provide these newly formed vasa vasorum is also the medial layers are literally surrounded within the vessel wall, which is as large as significantly impaired in this animal by the influx of blood-born noxious sub- 33% of the main lumen’s endothelium in model,14 leading to saturation of the ves- stances or cells through the endothelium normal arteries.11 Several recent studies sel wall tissue and longer exposure time of both the main lumen and the vasa va- demonstrated that the vasa vasorum in- of medial and adventitial cells to proin- sorum. This indicates that microvascular deed serve as important entry ports for flammatory and proatherogenic sub- endothelial dysfunction at the level of the influx of cellular and noncellular stances. Furthermore, functional data vasa vasorum in the early phases of proinflammatory and proatherosclerotic suggest that in the porcine animal model, atherogenesis may amplify alterations

Figure 2. Volume-rendered microcomputed tomography images of the two types of arterial coronary vasa vasorum (examples are from porcine coronaries that represent human anatomy). The main coronary artery lumen and major branches are displayed in gray, vasa vasorum in yellow. Vasa vasorum interna (left) arise directly from the main coronary artery lumen and arborize into the vessel wall. Vasa vasorum externa (the most prevalent type of arterial vasa vasorum; right) originate from major branches of the coronary artery and dive back into the main coronary’s vessel wall.

2838 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 2836–2842, 2007 www.jasn.org SPECIAL ARTICLE within the vessel wall that disrupt its ho- tion, and shorter cumulative event-free receptor (VEGF-R2/KDR) is the current meostasis and promote atherogenesis. survival.31 In contrast, in patients with standard. In addition, recent studies It is not surprising, then, that increas- acute coronary syndromes (acute myo- have suggested an important distinction ing evidence suggests that these “vessels cardial infarction and unstable angina between EPC purely identified by cell of vessels” (vasa vasorum) play an im- pectoris), the majority of published liter- surface antigens or by their capability to portant role in the initiation, progres- ature suggests that the number of EPC is form discrete colonies of endothelial sion, and complications of atherosclero- increased.33,34 This increase has been ob- cells in culture35,36 (CF-EPC). Hence, a sis.18–20 Moreover, the spatial vasa served within a few hours from the onset reduction in the number of circulating vasorum density and distribution in dif- of the acute event until 2 mo after.33 EPC may not necessarily reflect in re- ferent vascular beds (carotid, coronary, Most likely, the acute increase in EPC duced potential for neovascularization renal, and femoral arteries) are associ- mobilization is caused by concomitant or re-endothelialization. ated with their propensity to develop release of inflammatory and hematopoi- Studies in patients with diabetes have atherosclerosis.21,22 etic cytokines (e.g., VEGF, IL-8, stromal- shown that recruitment of EPC to the In summary, early microvascular en- derived factor-1). Alas, what looks like a vascular injury site is impaired, indicat- dothelial dysfunction has a significant reasonable, clear difference of EPC ing that endothelial dysfunction, which impact on vessel wall homeostasis, lead- counts in stable (low EPC) versus unsta- is well documented in patients with dia- ing to a proatherosclerotic environment ble (high EPC) coronary syndromes sec- betes, may play a role in this scenario.37 even before the development of visible ondary to a release of mobilizing cyto- In addition, animal models of decreased atherosclerotic lesions. The question kines during the stress situation was NO activity show impaired functionality whether vasa vasorum neovasculariza- lately challenged by a study by Guven et of EPC in repairing the vascular injury tion is beneficial or detrimental, whether al.,35 who found that in patients with an- site.38 Another potential role for the EPC it is a trigger or just an epiphenomenon giographically documented significant from mesenchymal origin may be in de- of atherosclerosis, is still not fully an- coronary artery disease, the number of termining the kind of vascular repair swered; however, it is evident that the se- EPC was actually increased and EPC such as coronary calcification, with EPC verity of atherosclerosis correlates with numbers correlated with maximum an- that carry an osteogenic potential.39 vasa vasorum neovascularization,23–26 giographic stenosis severity. However, The extension of endothelial dysfunc- and animal models of atherosclerosis in- this study used more rigorous histologic tion may be seen in two distinct ways. On dicate that inhibition of vasa vasorum and flow cytometric techniques to quan- the one hand it may extend into bone neovascularization reduces plaque size tify EPC as well as an angiographic defi- marrow microvascular endothelial dys- and influx of proinflammatory cells.13,27 nition of coronary artery disease, which function (i.e., the release of EPC from the Clearly, vasa vasorum may be a very in- makes it hard to compare directly with bone marrow is impaired as a result of teresting future therapeutic target. earlier, potentially conflicting studies. loss of efferent vessels). On the other In all observations, however, it is cru- hand, cardiovascular risk factors and ag- cial to exclude potential cofounders that ing may lead to impaired mobilization, MICROCELLULAR ENDOTHELIAL can influence the EPC counts. These in- migration, proliferation, and survival of DYSFUNCTION OF EPC clude comorbidities, current medical EPC, as well as to dysfunctional EPC that therapy, and the interval between acute are thus proatherogenic.40 Of course, Bone marrow–derived EPC generated stress events (e.g., acute myocardial in- both mechanisms may coexist; therefore, substantial interest and have been the fo- farction, unstable angina pectoris, other endothelial dysfunction and the abnor- cus of basic and clinical cardiovascular significant medical conditions) and pre- mal repair may also be characterized by research in recent years. Emerging evi- vious coronary interventions. Further- the modification of the number and dence suggests that EPC play an impor- more, is seems that potentially conflict- function of proatherogenic EPC pro- tant role in the repair of endothelial in- ing data may be due at least in part to duced and released into systemic circula- jury and restoring local endothelial methodologic differences, especially re- tion; therefore, both the vessel wall (vasa function.28,29 Conversely, a reduction of garding the definition of EPC and coro- vasorum) and circulating EPC are poten- EPC numbers has been shown to be as- nary artery disease. Future studies will tially impaired in the setting of endothe- sociated with endothelial dysfunction30 have to clarify the role of the various lial dysfunction. Moreover, these two and adverse cardiovascular out- types of EPC in well-defined clinical sce- systems might be related. The discrep- comes.31,32 narios, especially because EPC may be- ancy between the number of circulating In stable coronary artery disease (con- come a future therapeutic target. EPC and their colony-forming capacity firmed by coronary angiography), a low Despite the ongoing controversy raises the hypothesis that reduction of number of EPC (CD34ϩ/VEGFR-2ϩ)is about how best to classify EPC, identifi- peripheral EPC may reflect the impair- associated with a higher risk for cardio- cation of hematopoietic cell surface ment of re-endothelialization at the in- vascular death, first major cardiovascu- markers such as CD34 and CD133 and jury site, whereas the increase in the frac- lar event, revascularization, hospitaliza- the vascular endothelial growth factor tion of CF-EPC may confer increased

J Am Soc Nephrol 18: 2836–2842, 2007 Endothelial Dysfunction: A New View 2839 SPECIAL ARTICLE www.jasn.org propensity for neovascularization that EPC may also be detrimental in a pa- New diagnostic techniques that are may exhibit in vasa vasorum. Whereas tients with existing complex lesions; designed to detect the early manifesta- vasa vasorum neovascularization may be plaque rupture and acute lethal throm- tion of atherosclerosis are needed. These detrimental as a result of the increased bosis may be a consequence.18 Con- new diagnostic techniques should in- number of entry ports for proatheroscle- versely, experimental data have demon- clude the assessment of endothelial func- rotic substances into the vessel wall, re- strated that intravenous transfusion of tion, the number and function of EPC, endothelialization of the vascular injury EPC may reduce neointima formation.44 and the degree of inflammation and neo- site with EPC would be beneficial. The same complexity is true for a po- vascularization. On the basis of these Hence, the observations of reduced EPC tential antiangiogenic treatment to prevent novel diagnostic tests, a new therapy that in coronary artery disease patients in one vasa vasorum neovascularization. The cur- is directed toward the mechanism of ath- study31 but increased colony-forming rent data are equivocal,45 and the response erosclerosis in addition to the correction EPC in another35 might not be a true to therapy may depend on the vascular of risk factors may attenuate disease pro- contradiction. Whereas the former ex- beds involved. One possible solution might gression and complications. plains the failure to repair the injured en- be local, specifically designed drug delivery dothelium or alternatively re-endotheli- (e.g., through resolvable stents46) that may alization with inadequate EPC (e.g., with not have long-term adverse effects. ACKNOWLEDGMENTS osteogenic potential or other dysfunc- There is an increasing body of evi- tions), the latter explains vasa vasorum dence demonstrating the pleiotropic ef- This work was supported in part by the Na- neovascularization associated with pro- fects of hydroxymethyl glutaryl CoA re- tional Institutes of Health (grants HL6984 gression of atherosclerosis. ductase inhibitors (statins); especially and HL77131) and the Mayo Clinic College It is obvious that the atherosclerotic their anti-inflammatory and antiangio- of Medicine. process is very complex and affected by genic effects certainly make this a possi- the interactions among many systems; ble approach.47 In addition, several stud- therefore, vasa vasorum may well repre- ies have shown that statins increase the DISCLOSURES sent the tubes that deliver the progenitor mobilization of bone marrow–derived None. cells into the vessel wall and their neovas- EPC, possibly through the Akt signaling cularization may enhance delivery.41 pathway.48,49 This increase is reported to Vasa vasorum neovascularization may be comparable to the effect of VEGF on REFERENCES also be detrimental if this facilitates de- EPC mobilization. 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