Angiogenesis and Endothelial Cell Repair in Renal Disease and Allograft Rejection
Marlies E.J. Reinders*,,
Ton J. Rabelink and
David M. Briscoe*
* Transplant Research Center, Division of Nephrology, Department of Medicine, Children’s Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; and Department of Nephrology and Hypertension, University Medical Center Leiden, Leiden, The Netherlands
Address correspondence to: Dr. David M. Briscoe, Division of Nephrology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-355-6129; Fax: 617-730-0130; E-Mail: david.briscoe{at}childrens.harvard.edu
This review discusses the concept that the turnover and replacementof endothelial cells is a major mechanism in the maintenanceof vascular integrity within the kidney. CD133+CD34+KDR+ endothelialcell progenitor cells emigrate from the bone marrow and differentiateinto CD34+KDR+ expressing cells, which are present in high numberswithin the circulation. These progenitor cells are availablefor recruitment into normal or inflamed tissues to facilitateendothelial cell repair. In several forms of renal disease,proinflammatory insults mediate oxidative stress, senescence,and sloughing of endothelial cells. A lack of growth factorsor an inefficient recruitment of endothelial cell progenitorsresults in hypoxic tissue injury and accelerates the processof chronic renal failure. Augmentation of vascular repair bythe provision of growth factors such as vascular endothelialgrowth factor or by the transfer of progenitor cells directlyinto the kidney can be protective and prevent ongoing interstitialdamage. In allografts, persistent injury results in excessiveturnover of graft vascular endothelial cells. Moreover, chronicdamage elicits a response that is associated with the recruitmentof both leukocytes and endothelial cell progenitors, facilitatingan overlapping process of inflammation and angiogenesis. Becausethe angiogenesis reaction itself is proinflammatory, this processbecomes self-sustaining. Collectively, these data indicate thatangiogenesis and endothelial cell turnover are important inrenal inflammatory processes and allograft rejection. Manipulationof the response may have therapeutic implications to protectagainst injury and chronic disease processes.
Angiogenesis is well established to be a characteristic componentof immune inflammation and has been shown to be of pathologicsignificance in ischemic and chronic inflammatory diseases,including diabetes, retinopathy, atherosclerosis, allograftrejection, coronary artery disease, and myocardial infarction(1–13). Moreover, several acute and chronic renal diseases,including ischemic nephropathy, glomerulonephritis, and interstitialnephritis, were found recently to be associated with angiogenesis,and there is interest in the concept that manipulation of thisresponse can attenuate the disease process (9,14–19).In the course of acute inflammation, leukocytes and plateletsinduce and/or deliver angiogenesis factors into the local site,mediate the proliferation of local endothelial cells, and/orfacilitate the recruitment of endothelial progenitor cells (EPC)(20–22). In this circumstance, the resolution of the acuteresponse coincides with a resolution of the healing angiogenesisresponse. In contrast, in chronic inflammation, in which tissuedestruction and mononuclear cell infiltration are dominant,the persistent delivery and local expression of angiogenesisfactors can serve to sustain the angiogenesis response (4,12,23–26).In its normal guise, angiogenesis is thought to facilitate therepair of injured tissues and to restore oxygenation. In diseasessuch as glomerulonephritis, ischemic nephropathy, and tubulointerstitialfibrosis and in the aging process, accelerated attrition ofthe microvasculature as a result of inefficient delivery ofangiogenesis factors and/or EPC results in ongoing and persistenthypoxia, which can result in further tissue destruction (9,27–29).In this circumstance, it has been demonstrated that deliveryof angiogenesis factors and the augmentation of the angiogenesisresponse can be therapeutic to promote recovery. Conversely,in chronic diseases such as atherosclerosis and chronic allograftvasculopathy (CAV), persistent angiogenesis promotes the ongoingrecruitment of inflammatory cells, which in turn sustains theangiogenesis reaction (3, 5, 8, 24, 30). In this scenario, ithas been proposed that antiangiogenesis therapy can attenuatedisease and is therapeutic. Collectively, these observationssuggest that the process of angiogenesis is interrelated withacute and chronic inflammatory disease processes and that manipulationof the reaction may have therapeutic implications.
In this review, we discuss the intriguing mechanistic and functionalinterrelationship between endothelial cell repair mechanismsand the angiogenesis reaction in renal inflammatory diseasesand allograft rejection. We discuss several processes and mechanismsby which the EPC can be recruited into local sites to facilitaterepair. Moreover, we identify some diseases in which the expressionof angiogenesis factors and the angiogenesis reaction are lackingand others in which the persistent expression of growth factorsand the angiogenesis reaction may in itself be of pathologicsignificance.
The integrity of the vascular endothelium is critical for thehealth of an organ and is determined by the balance betweenendothelial turnover and repair. After an inflammatory insult,damaged endothelial cells slough into the circulation, and replacementoccurs via the induced proliferation of neighboring endothelialcells and/or by the recruitment of EPC from the circulation.In recent years, it has become evident that an important sourceof endothelial cells for repair comes from the circulation andthat "vascular health" is dependent on an ample supply of thesecell types. In a recent study (31), it was found that levelsof EPC in the circulation are indicative of risk for vasculardisease. Patients with the highest numbers of circulating EPCwere least at risk for coronary artery disease, suggesting thatcirculating EPC levels and the maintenance of vascular integrityclearly are associated and may be of major clinical relevance(32). However, it is important to note that, at present, ourunderstanding is by association, and more research will be neededto understand the mechanism. For instance, several studies havefound that this pattern is not true for dialysis patients, inwhom several insults (hypertension, diabetes, oxidative stress,etc.) are associated with an increase in circulating EPC andan increased risk for acute cardiovascular events (33). Also,nitric oxide (NO) is known to mediate the release of EPC frombone marrow (34), and there is a well-established reductionin the bioavailability of NO in association with atherosclerosis.Therefore, reduced circulating EPC in association with atherosclerosissimply may be reflective of a common factor (e.g., NO) and/orsuggest more complex interactions with proatherogenic mediators.
Growing evidence suggests that the bone marrow is a rich sourceof immature EPC and that bone marrow-derived EPC circulate constantlyin the blood, albeit in low numbers. Circulating EPC can berecruited into vascular beds to maintain normal physiologichomeostasis/repair. They also may contribute to immune angiogenesisin the setting of chronic inflammation (see below), and severalstudies have indicated that they play an important role in theformation of new blood vessels in ischemia-reperfusion (35).
Populations of EPC express different cell surface receptors,which vary according to their stage of maturation. The receptorsCD34 and the vascular endothelial cell growth factor receptor-2(VEGFR-2), called KDR, were used initially to characterize circulatingEPC (36), but additional studies have determined that anothermolecule, CD133, also is present on EPC at an earlier stagein their development (37, 38). Therefore, although progenitorcells express CD133 at their earliest stage of maturation, itis lost in the course of maturation, whereas the expressionof CD34 and KDR persists. Also, it has been found that CD14is expressed on some immature CD34+ KDR+ EPC (39), whereas othermolecules identify endothelial cells at both early and laterstages of maturation. These include VE-cadherin, von Willebrandfactor, CD31, and Ulex (36–40). Together, these observationssuggest that EPC are a heterogeneous population of cells thatcirculate in the blood at different stages of maturation, eachwith the potential for differentiation into mature endothelialcells.
Regardless of maturation or cell surface phenotype, all EPChave the capacity to be recruited into sites of injury to maintainvascular integrity (Figure 1). Moreover, it is proposed thatthe predominant cell type that mediates repair is the most numerousEPC within the circulation (the CD14+CD34+KDR+ EPC), as it ismore readily available for recruitment (19, 37, 39). Vascularinjury that results in the exposure of naked basement membranesand the associated recruitment of platelets and the releaseof cytokines, chemokines, and growth factors provides for cellularand molecular mechanisms that further enhance the local infiltrationof circulating leukocytes (including circulating CD34+ KDR+progenitor cells) into a site of injury (20, 41–43). Oncepresent in an injured vascular bed, EPC stimulate neighboringendothelial cells to divide and facilitate endothelial repairand angiogenesis in vivo (41).
Figure 1. Illustration of the ability of circulating endothelial cell progenitor cells (EPC) to mediate vascular endothelial cell repair.
A clinically important extension of these observations is thatthe systemic or local tissue administration of bone marrow orEPC into patients after an inflammatory reaction can be therapeuticto prevent tissue destruction/scarring and promote healing.In experimental animals, the transfer of EPC after limb or cardiacischemia has been established to be therapeutic (35, 44–48).Early clinical trials in humans have hinted that patients withcardiac disease might benefit from the local administrationof enriched bone marrow-derived EPC after acute myocardial infarction(44–46). Furthermore, as is discussed next, in experimentalkidney diseases, including ischemic nephropathy, interstitialnephritis, and glomerulonephritis, the provision of EPC or angiogenesisfactor(s) can promote neoangiogenesis and can attenuate theseverity of disease.
Development of Angiogenesis in Immune Inflammation
Although hypoxia is the main physiologic stimulus for the formationof new capillaries and for the recruitment of EPC, it also hasbeen shown that endothelial cells proliferate and that angiogenesisis prominent in association with inflammation, even in the absenceof hypoxia. Moreover, several studies have demonstrated thatthe angiogenesis reaction and inflammatory processes are interactiveand interrelated (3, 4, 24). Some proinflammatory cytokineshave angiogenic properties, and some potent angiogenesis factors,such as VEGF, have proinflammatory properties (Figure 2). Intheir original studies to define the ability of leukocytes toinduce angiogenesis, Sidky and Auerbach (21, 22) observed thatthe direct local infusion of spleen cells into the skin of nudemice resulted in the formation of characteristic neovesselsthat showed tortuosity and loop formation, similar to the angiogenesisobserved in tumors. The angiogenesis reaction was reproducible,occurred within 3 to 6 d, and was dose dependent, showing alinear correlation between the number of induced vessels andthe dose of injected spleen cells. The molecular basis for theseobservations now are understood and in part involves the secretionof several proangiogenic mediators, including VEGF (4, 30, 49),TNF- (25), TGF-, and NO (50). It is interesting that some ofthese factors have been found to function in part by stimulatingVEGF production, suggesting that VEGF may be a common mediatorfor the initiation of leukocyte-induced angiogenesis (51–53).Furthermore, whereas products of activated monocyte/macrophagesoriginally were reported to be most potent in their abilityto induce angiogenesis (25, 50, 54–56), it now is knownthat activated T cells also are a major source of angiogenesisfactors (57–59) and that they stimulate a profound VEGF-inducibleangiogenesis reaction (53, 60). Consistent with these observations,the expression of angiogenesis growth factors typically is foundin tissues with enhanced inflammation. It therefore is not surprisingthat angiogenesis frequently is associated with inflammatoryconditions and that angiogenesis and inflammation induce overlappingand interactive processes.
Figure 2. Central role for vascular endothelial growth factor (VEGF) in immune-mediated angiogenesis. VEGF is well established as an angiogenesis factor via its direct effects on endothelial cells. It also has potent proinflammatory properties, suggesting that it also may elicit angiogenesis via the recruitment of circulating leukocytes.
Another important observation is that angiogenic reactions (evenin tumors) typically are associated with inflammatory infiltrates.Using videomicroscopy, Jain’s group (61–63) hasdefined this interrelationship elegantly, and they reportedthat neovessels are "sticky" and elicit rolling and stable arrestinteractions with leukocytes. It now is established that neovesselsat sites facilitate the recruitment of leukocytes, in part viadistinct molecular receptor-ligand interactions, such as thosethat are mediated by adhesion molecules and chemokines (62,64, 65). Also, some angiogenesis factors, most notably VEGF,can function as a major proinflammatory cytokine (30). VEGFinduces the expression of the adhesion molecules E-selectin,intercellular adhesion molecule 1 and vascular cell adhesionmolecule 1 and the chemokines IL-8 and monocyte chemoattractantprotein-1 on endothelial cells. Moreover, VEGF is directly chemoattractantfor monocytes and can promote inflammation via its potent effectto enhance vascular permeability (30, 62, 64, 66, 67). In ourown studies that have addressed the proinflammatory functionof VEGF, we also identified its ability to augment IFN--inducibleexpression of the T cell chemoattractant chemokine IP-10 andIP-10-dependent leukocyte recruitment (68). Collectively, theseobservations indicate that there is a clear molecular basisfor the interrelationship between angiogenesis and inflammationand that each process cannot be considered in isolation. Moreover,it is likely that VEGF represents a potent intermediary betweeneach of these reactions.
Exposure of endothelial cells to adverse inflammatory conditionsincreases endothelial cell apoptosis and turnover. For example,in renal transplant patients, several studies have shown increasedlevels of CD146 necrotic endothelial cells (69) (discussed inmore detail below). Although mature endothelial cells have thecapacity to proliferate and replace dying cells, chronic exposureto an inflammatory milieu and the associated oxidative stresshave been shown to lead to premature replicative senescenceand limit this form of endothelial repair. Chronic oxidativestress compromises telomere integrity and accelerates the onsetof senescence in human endothelial cells (70). Eventually, endothelialcell death and shedding may lead to disturbances of the endothelialmonolayer, necessitating endothelial cell repair. Therefore,in the setting of chronic inflammation, several factors elicitdamage, and disease may reflect in part a balance between thedegree to which loss occurs and the ability of EPC to facilitaterepair and maintain tissue homeostasis. Hypoxia, VEGF, basicfibroblast growth factor, angiopoietin-1, placental growth factor,and stromal cell-derived growth factor-1 all have been shownto induce the mobilization and recruitment of EPC into the localsite (20, 41, 43, 71). Furthermore, local EPC release growthfactors, including VEGF, G-CSF, and GM-CSF, which are knownbe chemotactic for EPC and facilitate additional migration ofEPC into the site. Therefore, once effective repair mechanismsoccur, chronic disease also may be related to amplificationloops that serve to maintain the local angiogenic microenvironment.
Collectively, all of these findings indicate that the recruitmentof EPC into local tissue sites can facilitate endothelial repairand vasculogenesis. The mechanisms just discussed describe howEPC might be recruited into sites of inflammation. Furthermore,because CD34+ cells also have the capacity to differentiateinto macrophages and dendritic cells after treatment with specificcytokines (72, 73), the inflammatory milieu may determine whethera CD34+ stem cell matures into either an EPC or a dendriticcell. For instance, treatment of CD34+ cells with GM-CSF andIL-4 promotes their differentiation into dendritic cells (72,73), whereas the presence of VEGF and other endothelial cellgrowth factors in cell culture medium enhances differentiationinto mature endothelial cells (36, 37, 74). Some recent observationsindicated that purified CD34+KDR+ EPC can differentiate intodendritic cells (T.J.R., unpublished observations, 2005). Therefore,the overlap between angiogenesis and inflammation may be morecomplex and inasmuch as the type of inflammation or tissue environmentmay be a major determinant of the response.
Endothelial Cell Progenitors and Angiogenesis in Renal Inflammatory Disease
The development of tubulointerstitial fibrosis is characteristicof chronic renal disease, and inhibition of its progressionhas been proposed to be of major importance in the preservationof renal function. In both experimental animal models and inhumans, it has been shown that there is significant loss ofperitubular capillaries as well as defective capillary repairin association with the development of interstitial fibrosis(75–77). Even in the normal aging process, it has beenshown that the loss of glomerular endothelium is associatedwith progressive renal impairment (27, 77). It is importantto note that the angiogenic growth factor VEGF plays an importantrole in maintaining glomerular integrity under normal physiologicconditions. VEGF is expressed by podocytes, tubular epithelialcells, and endothelial cells (78–81), and increases inVEGF expression are well established to be functional for renalvasculogenesis and renal development in the embryo (82–84).In addition, in experimental models, it has been shown thatpostnatal glomerular capillary function is under strict controlby VEGF (79, 85). When intraglomerular VEGF levels decreasein a transgenic mouse, capillary endothelial cells swell, capillaryloops collapse, and proteinuria develops (79, 86). Moreover,it has been found that conditional VEGF isoform knockout micehave impaired glomerular filtration (82). Consistent with theseobservations, when VEGF function is inhibited in vivo with sFlt-1(the soluble form of VEGFR-1) or with anti-VEGF antibodies,proteinuria develops, and it has been found that this processis associated with rapid glomerular endothelial cell detachmentand downregulation of nephrin, a key epithelial protein in theglomerular filtration apparatus (87, 88). Furthermore, the treatmentof pregnant rats with sFlt-1 has been found to result in hypertension,proteinuria, and glomerular endotheliosis, the classic lesionof preeclampsia (89). Therefore, decreases in local intrarenalconcentrations of VEGF by VEGF antagonists under normal conditionswill disrupt glomerular integrity and the glomerular permselectiveproperties.
In models of aging-associated renal disease, the loss of expressionof the angiogenesis factor VEGF in podocytes and tubules hasbeen found to correlate with a reduction in the number of proliferatingendothelial cells (27). It is proposed that the loss of theintrarenal vasculature results in impaired delivery of oxygenand nutrients to the tubules, which in turn results in chronicischemia and cell death. Several regions of the medulla normallyexist in some degree of hypoxia and low oxygen tension; therefore,any defect in the vasculature will disrupt the high metabolicdemands of the tubular epithelial cell and may promote celldeath. Therefore, the peritubular capillary network of vesselsplays a major role in the maintenance of renal function andhemodynamics. The progressive loss of intraglomerular endothelialcells and/or peritubular capillaries may be a primary factorin the development of chronic renal disease (9, 15, 88).
Some chronic renal disease processes that are associated withendothelial cell loss and peritubular capillary dropout canbe attenuated by the augmentation of angiogenesis or by thetransfer of EPC into the kidney. Johnson’s group (9, 15,16, 27) performed an extensive analysis of the degree to whichintraglomerular endothelial cell and peritubular capillary lossis a component of renal insufficiency. Using the remnant kidneymodel, this group reported that, after injury, there is an initialearly angiogenic response with increases in the proliferationof peritubular and glomerular endothelial cells (15). In addition,early after injury, there is an increase in the expression ofVEGF (mainly in tubules and glomerular podocytes), but thisincrease in VEGF expression is transient. A subsequent decreasein VEGF expression is associated with a decrease in endothelialcell proliferation, and it was found that the degree of glomerularand peritubular capillary loss correlates with the severityof glomerulosclerosis, interstitial fibrosis, and tubular atrophy(16, 27). Furthermore, they found that there was an increasein the expression of the antiangiogenesis molecule thrombospondin-1at these later times (4 to 8 wk) after injury. It was proposedthat the increase in thrombospondin-1 expression, the loss ofVEGF expression, and the associated capillary loss contributeto the development of glomerulosclerosis and interstitial fibrosis(27). In another report, this same group found that the lackof persistence of VEGF expression was of pathophysiologic significancein the progression of renal insufficiency. The systemic administrationof VEGF into rats after renal injury enhanced angiogenesis withinthe kidney and reduced renal fibrosis and stabilized renal function(16).
Endothelial cell loss and dysregulated repair also have beenfound to be of pathophysiologic significance in anti-glomerularbasement membrane models of glomerulonephritis and chronic renaldysfunction. In the well-established anti-Thy-1.1 model of acuteglomerulonephritis, it was shown that glomerular endothelialcell proliferation is of importance in the repair of capillaries(29) and that the administration of VEGF promotes capillaryrepair and prevents global sclerosis and subsequent chronicrenal failure (28). Moreover, blockade of VEGF with a VEGF antagonistinhibited capillary repair and enhanced the progression of renalimpairment after the induction of mesangioproliferative nephritis(87). Also in another study, the administration of VEGF as aninterruption protocol after injury was already established withinthe kidney resulted in an increase in peritubular capillarydensity and improved renal function and was associated withless fibrosis (90). Collectively, all of these studies havedemonstrated that progressive capillary loss may be a primaryfactor in the development of chronic renal insufficiency andthat the administration of VEGF can attenuate both the degreeof capillary loss and the degree of interstitial disease/renaldamage.
Although the systemic administration of VEGF has been shownto mobilize endothelial cell stem cells (91, 92), none of thesereports addressed whether this is an underlying mechanism bywhich VEGF therapy improves renal function after injury. Uchimuraet al. (93) assessed whether the administration of bone marrowmononuclear cells could limit glomerular endothelial cell injuryin the anti-Thy-1.1 model of nephritis. They cultured bone marrowin medium to enrich EPC and injected the cells into the leftrenal vessels while leaving the right kidney unmanipulated.They found that the bone marrow-derived stem cells incorporatedinto the glomerular endothelial bed, enhanced repair, and reducedendothelial injury compared with the unmodified right kidney(93). Moreover, other studies have demonstrated that glomerularendothelial cell repair after the induction of glomerulonephritisinvolves the recruitment of bone marrow-derived EPC into thekidney (94, 95). It therefore is proposed that the mobilizationof bone marrow-derived EPC can be used as a therapeutic approachin the treatment of progressive renal failure to facilitateglomerular endothelial repair and to limit peritubular capillarydropout.
Nevertheless, it is important to note that some kidney diseases,such as diabetic nephropathy, have been associated with highlevels of VEGF and that forced overexpression of VEGF withinthe glomerulus can result in glomerulosclerosis and a histologicpattern that is similar to that seen in HIV nephropathy (79,96). Therefore, the augmentation of peritubular capillary repairand the preservation of angiogenesis by VEGF may not be a uniformmechanism to prevent chronic renal injury. For instance, highlevels of glucose are widely known to stimulate VEGF expression,and the proangiogenic growth factors IGF-1 and TGF- are knownto be expressed in early diabetic nephropathy. Moreover, treatmentof animals with anti-VEGF antibodies has been shown to improveearly renal dysfunction in a model of experimental diabetes(97); and inhibition of angiogenesis with the selective antiangiogenesisagents tumstatin (98) and endostatin (10) has been shown toattenuate glomerular hypertrophy, hyperfiltration, and proteinuriathat are associated with this disease. We suggest that furtherstudies will be necessary to understand the interrelationshipand balance between too little angiogenesis factor expression,which results in capillary loss and chronic hypoxia-inducibledamage, or too much angiogenesis factor expression, which mayresult in glomerular disease, hypertension, and vascular permeability.Nevertheless, the concept that angiogenesis and EPC can be usedas therapeutic agents to prevent chronic renal disease is noveland exciting and has great potential once they reach the clinic.
Endothelial Cell Repair/Turnover within Allografts
The process of transplantation results in several insults tothe donor endothelial cell that will require repair. All eventsin the peritransplantation period, including ischemia-reperfusioninjury and acute rejection mediate injury, and additional factorssuch as viral insults (e.g., cytomegalovirus [99]), immunosuppressivemedications, and chronic rejection, are well established toelicit chronic injury (23, 24). Woywodt et al. (69) evaluatedthe numbers of circulating CD146+ endothelial cells in patientsafter renal transplantation. CD146 is a marker of mature endothelialcells and likely represents sloughed endothelial cells in thesepatients. They found that patients with acute vascular rejectionhad the highest numbers of circulating CD146+ endothelial cellsand that all transplant recipients had significantly highernumbers than did healthy control subjects. In another study,they reported that patients who were treated with a calcineurin-sparingimmunosuppression protocol had higher circulating numbers ofendothelial cells than did healthy control subjects but thatthe difference was not statistically significant. These authorssuggested that the analysis of circulating CD146+ endothelialcells may be used as a biomarker of endothelial damage aftertransplantation. They also suggested that calcineurin inhibitorsdamage endothelial cells, thus facilitating turnover. Althoughthis is an important observation, they did not evaluate levelsof circulating CD34+KDR+ cells, which would be expected to mediaterepair in circumstances in which endothelial damage and sloughingare predominant (discussed in detail above). However, it ismost likely that recipient stem cells, including EPC, migrateinto allografts to facilitate angiogenesis and endothelial cellrepair (32). Factors (e.g., cytokines, chemokines, growth factors;discussed above) that govern the recruitment and integrationof EPC into endothelial cell beds all are present within allografts(100, 101).
Several studies have demonstrated that recipient EPC do migrateinto human allografts and have the ability to differentiateinto endothelial cells (102, 103). After human cardiac transplantation,this process occurs rapidly and is extensive. Quaini et al.(104) reported that after a median of 53 d, as many as 20% ofdonor vascular endothelial cells are replaced by recipient endothelialcells and that this process can begin as early as day 4 aftertransplantation. These observations suggest that after earlyischemia-reperfusion injury, acute rejection, or other insults,recipient EPC are most efficient to repair damaged vessels.In time, it is proposed that the endothelium within the graftbecomes "chimeric," consisting of endothelial cells that arederived from both the donor and the recipient. Lagaaij et al.(105) examined the replacement of damaged donor peritubularcapillary endothelium in human renal allografts. Similar tothe Quaini study, they found that donor endothelial cells arereplaced by recipient endothelial cells, but they noted thatthis repair mechanism was most prominent after acute vascularrejection (105). Another study, by Grimm et al. (106), notedthat recipient cells infiltrated renal allografts in the courseof chronic rejection. Collectively, all of these studies indicatethat circulating recipient EPC may be recruited into renal allograftsand that this repair process is most evident after microvasculardestruction that occurs in association with acute rejectionand in the course of the chronic rejection process (102, 103,105, 106).
It is not yet known whether endothelial chimerism within allograftsis a contributing factor for further allograft injury. A growingbody of literature indicates that mobilization of EPC may bebeneficial to allograft function by maintaining graft acceptanceand limiting downstream hypoxic tissue injury. However, it alsois possible that this reparative compensation and chimerismof endothelial cells might be a factor in the development ofchronic rejection by altering the immunologic properties ofthe graft. For instance, Heeger’s (107) group noted thatrecipient T cells can recognize allogeneic peptides that areprocessed and presented by recipient endothelial cells liningthe graft in a manner similar to the indirect pathway of allorecognition.This results in cell lysis and therefore ongoing damage (107).Because the indirect pathway of allorecognition is thought tobe dominant in chronic allograft rejection (108), this may suggestthat chronic replacement of donor endothelial cells by recipientendothelial cells will facilitate immunologic injury. Therefore,it will be important to understand how excessive turnover andperhaps neoangiogenesis, although potentially protective afteracute injury, may be of pathophysiologic significance for ongoinginjury and the development of chronic allograft rejection.
Chronic allograft rejection is associated with the expressionof adhesion molecules, chemokines, and growth factors such asVEGF (101, 109–111) that have the capacity to mediateEPC recruitment. Therefore, one could argue that excessive angiogenesiscould occur in the setting of chronic allograft rejection (24).Indeed, as discussed above, neovascularization is establishedto occur within allografts, and recipient endothelial cellsmay represent as many as 20% of the total number of endothelialcells within a failed allograft (104). In our own studies, wehave evaluated the process of recipient angiogenesis/reendothelializationusing a humanized mouse (huSCID) model. The SCID mouse is permissivefor the transplantation of human skin and for the adoptive transferof human peripheral blood leukocytes. In our studies, humanforeskin was transplanted onto SCID mice; after engraftment,peripheral blood leukocytes that were derived by plasmapheresisof human donors were adoptively transferred by intraperitonealinjection into the mouse. Seven days after transfer, the humanleukocytes were evident within the human skin graft but notin the mouse skin (30, 52, 60). In our analysis, we found thatthere was a marked local human angiogenesis response in theseskins at early times in the course of infiltration (Figure 3).The angiogenesis reaction was quantified by both videomicroscopyand immunohistochemistry and was found to be temporally andspatially associated with the leukocytic infiltrates (60). Furthermore,the angiogenesis response seemed to precede the developmentof vasculitis and microvascular destruction in association withfulminant rejection. Therefore, local tissue hypoxia likelywas not the primary stimulus for initiating the angiogenesisthat occurred early in these allografts. Rather, the angiogenesisreaction likely was initiated by leukocytes as is typical inleukocyte-induced angiogenesis.
Figure 3. Human skin was transplanted onto SCID mice and allowed to engraft for 6 wk as described (60). Human peripheral blood leukocytes (PBL; 3 x 108 cells) that were obtained by leukophoresis of volunteer donors were adoptively transferred into the mouse by intraperitoneal injection. After 3 to 7 d, the leukocytes were found to infiltrate the human skin but not the mouse skin. The process of infiltration was associated with a notable angiogenesis reaction that was temporally and spatially associated with the infiltrates. Illustrated is anti-human von Willebrand factor staining of human endothelial cells in skin that was harvested from SCID mice without transfer of PBL (left) or 14 d after transfer of PBL (right), showing marked angiogenesis in association with leukocyte recruitment.
Angiogenesis has been demonstrated within the intimal proliferatinglesion characteristic of CAV. Atkinson et al. (112) evaluatedthe expression of endothelial cell markers in CAV lesions fromfailed human cardiac transplants. They found that most vessels(approximately 90%) had evidence of neovessels predominantlywithin the middle portion of the neointima. In addition, theyfound that these neovessels were activated inasmuch as theyexpressed adhesion molecules and MHC class II, suggesting thatthe angiogenesis response itself may promote leukocyte recruitmentand activation (112). These observations are similar to thosepublished by others in experimental models. Tanaka et al. (113)evaluated the intima of the transplanted aorta in a hypercholesterolemicrabbit model and found that it contained prominent microvesselscompared with controls or animals that did not receive a transplant.They also noted that the increased capillary density was associatedwith T cell and monocyte infiltrates within the parenchyma ofcardiac transplants (113). Using an established Lewis into Fisherrat model of chronic cardiac allograft rejection (8, 114, 115),we also found that angiogenesis was present in large CAV lesions,again in association with mononuclear infiltrates. Because theneovascular response itself is proinflammatory, we questionedwhether it could sustain the growth of the intimal componentof the CAV lesion. We treated recipients with TNP-470, a syntheticfumagillin derivative that is well established to inhibit endothelialcell proliferation in vitro and in vivo, and found that it interruptedthe progression of CAV when given late. In contrast, it didnot prevent its development when given in the immediate posttransplantationperiod (8), suggesting that angiogenesis is functional in theprogression of CAV but is not associated with its initiation.Consistent with this interpretation, we also found that inhibitionof angiogenesis with endostatin, a most selective antiangiogenesisagent, interrupts CAV development in an established murine modelof CAV (M. Sho, A. Contreras, D.M.B., unpublished observations,2005).
We interpret all of these data to suggest that the mediatorsthat govern the recruitment of mononuclear cells into the intimaof large vessels also facilitate the recruitment of EPC andtherefore angiogenesis within the lesion. Moreover, EPC migrateto sites of vascular injury in response to T cell- and monocyte-derivedcytokines, chemokines, and growth factors that are known tobe present within the intimal lesion. Therefore, it is possiblethat chronic endothelial cell damage elicits a response thatis associated with the recruitment of T cells, monocytes, andEPC. The recruitment of the EPC is physiologic to repair thedisrupted vessel and to promote angiogenesis. Because the neovascularreaction is in itself proinflammatory, once present within theCAV lesion, the process will be self-sustaining. This explainswhy inhibition of angiogenesis in CAV (and perhaps in atherosclerosis)is therapeutic to limit disease progression.
An emerging body of literature has determined that circulatingEPC maintain vascular integrity and are functional in the repairof damaged tissues. EPC are recruited into the kidney in thehealing phase of renal inflammation, and a deficiency in thisprocess can result in persistent cell death and the developmentof chronic disease. Early studies have indicated that augmentationof EPC-dependent repair by the provision of VEGF or by the directtransfer of EPC into the kidney can augment healing and canlimit ongoing disease. In contrast, in allografts, ongoing inflammationfacilitates the persistent recruitment of EPC that may resultin a marked angiogenesis reaction, especially within the intimalproliferating lesion of large vessels with CAV. Because EPCare a heterogeneous population of cells, in future studies,it will be important to understand their nature and tissue selectivityand whether select growth factors, cytokines, and cell surfacemolecular interactions within tissues facilitate different differentiationpatterns. To this end, we conclude by noting some interestingobservations about the hormone erythropoietin, which is commonlyused in patients with chronic renal failure. Among its biologiceffects, erythropoietin is a potent physiologic stimulus forthe mobilization of stem cells (116, 117), including EPC (118),and it has been found to augment neovascularization in vitroand in vivo (118). Erythropoietin receptors are present on culturedhuman endothelial cells, and activation of postreceptor signalingelicits a protective antiapoptotic and promigratory angiogenicphenotype (118–120). In animal models, erythropoietinhas been shown to stimulate angiogenesis in association withischemia and acute inflammation (118), and in humans, it markedlyincreased the number of CD34+ circulating EPC (121). Therefore,the use of erythropoietin in humans with chronic renal diseaseor chronic allograft rejection might enable novel studies tobe performed on the role and potential importance of mobilizedEPC as a therapeutic agent.
Finally, we suggest that in future studies, it will be importantto understand how excessive turnover and angiogenesis are protectiveafter acute injury but are pathologic in chronic disease states,especially within the vasculature. Nevertheless, the growingliterature indicates that angiogenesis and endothelial turnoverare most important concepts for our understanding of renal diseaseand allograft rejection and that manipulation of the responsewill have major consequences for therapeutics in the future.
Acknowledgments
Many of the studies discussed in this review were supportedby National Institutes of Health grants AI46756, AI50157, andHL74436.
We acknowledge members of our laboratories and our collaboratorsfor their constant scientific input and efforts on our studiesof angiogenesis. Specific thanks to Drs. Alan Contreras, MarkDenton, Olivier Dormond, Zdenka Haskova, Rakesh Jain, KashiJavaherian, Karen Moulton, Debabrata Mukhopadhyay, SoumitroPal, Mohamed Sayegh, and Masayuki Sho, who contributed to severalof the studies described in this report.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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(25), TGF-
, and NO (50). It is interesting that some of these factors have been found to function in part by stimulating VEGF production, suggesting that VEGF may be a common mediator for the initiation of leukocyte-induced angiogenesis (51–53). Furthermore, whereas products of activated monocyte/macrophages originally were reported to be most potent in their ability to induce angiogenesis (25, 50, 54–56), it now is known that activated T cells also are a major source of angiogenesis factors (57–59) and that they stimulate a profound VEGF-inducible angiogenesis reaction (53, 60). Consistent with these observations, the expression of angiogenesis growth factors typically is found in tissues with enhanced inflammation. It therefore is not surprising that angiogenesis frequently is associated with inflammatory conditions and that angiogenesis and inflammation induce overlapping and interactive processes. 
-inducible expression of the T cell chemoattractant chemokine IP-10 and IP-10-dependent leukocyte recruitment (68). Collectively, these observations indicate that there is a clear molecular basis for the interrelationship between angiogenesis and inflammation and that each process cannot be considered in isolation. Moreover, it is likely that VEGF represents a potent intermediary between each of these reactions. 
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Endothelial Cell Progenitors and...
Endothelial Cell Repair/Turnover...
