6. Gold R, Hartung HP, Toyka KV. Animal models for autoimmune demyelinating disorders of the nervous system.Mol Med Today.2000;6: 88 –91
7. Rostami AM. Guillain-Barre syndrome: clinical and immunologic as-pects.Springer Semin Immunopathol.1995;17:29 – 42
8. Sharief MK, McLean B, Thompson EJ. Elevated serum levels of tumor necrosis factor-alpha in Guillain-Barre syndrome.Ann Neurol.1993;33: 591–596
9. Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases.Neurology.1998;51(6 suppl 5):S2–S8
10. Hughes RA, Raphael JC, Swan AV, Doorn PA. Intravenous immuno-globulin for Guillain-Barre syndrome.Cochrane Database Syst Rev.2004; (1):CD002063
11. Korinthenberg R, Schessl J, Kirschner J, Schulte Moenting J. Intravenous immunoglobulin in the treatment of childhood Guillain-Barre´ syndrome: a randomized trial.Pediatrics.2005;116:8 –14
12. Gurses N, UJsal S, Cetinkaja F, Islek I, Kalayci AG. Intravenous gamma globulin treatment in children with Guillain-Barre syndrome.Scand J Infect Dis.1995;27:241–243
13. Zafeiriou DI, Kontopoulos EE, Katzos GS, Gombakis NP, Kanakoudi FG. Single dose immunoglobulin therapy for childhood Guillain-Barre syndrome.Brain Dev.1997;19:323–325
14. Koul R, Chacko A, Ahmed R, Varghese T, Javed H, Al-Lamki Z. Ten-year prospective study (clinical spectrum) of childhood Guillain-Barre syndrome in the Arabian peninsula: comparison of outcome in patients in the pre- and post-intravenous immunoglobulin eras.J Child Neurol.
2003;18:767–771
15. Sekul EA, Capler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy; frequency and risk factors.Ann Intern Med.1994;121:259 –262
Understanding Abnormalities in
Vascular Specification and
Remodeling
ABBREVIATIONS. MMP, matrix metalloproteinase; bFGF, basic fibroblast growth factor; ECM, extracellular matrix; VEGF, vascu-lar endothelial growth factor; TGF, transforming growth factor; TIMPs, tissue inhibitors of matrix metalloproteinase.
A
ccurate classification, diagnosis, manage-ment, and treatment of vascular lesions in children can be hindered by the wide range of clinical presentations and varying clinical course of these lesions. In this issue ofPediatrics, Marler et al1 report novel findings that elevated levels of an-giogenesis-related proteins, specifically high molec-ular weight matrix metalloproteinases (MMPs) and basic fibroblast growth factor (bFGF), can be detected in the urine of children with vascular anomalies and can mark clinical progression of these lesions. These findings suggest that a noninvasive test can be de-veloped to characterize aggressive vascular malfor-mations and tumors and provide additional evidence that antiangiogenic agents may be useful for the treatment of these lesions.To approach diagnosis and management of con-genital vascular lesions rationally, an understanding of the basic cellular, molecular, and genetic mecha-nisms of blood vessel formation is required. Recent advances in the field of vascular biology have con-tributed to our knowledge of how blood vessels are assembled during early embryonic development. Blood vessel morphogenesis involves discrete steps in continuum that are regulated by specific signaling pathways involving soluble effectors, cytokines and their receptors, proteases, and extracellular matrix (ECM) components. These various pathways control integral events that contribute to the formation of a functional vasculature including endothelial and mural cell (pericyte/smooth muscle cell) differentia-tion, cell proliferation and migradifferentia-tion, and the speci-fication of arterial, venous, and lymphatic fate. Dys-regulation of these processes can result in vascular malformations affecting 1 or multiple vascular types including capillary, arterial, venous, lymphatic, or arteriovenous channels.
BLOOD VESSEL FORMATION
During embryonic development, blood vessels form de novo from endothelial progenitors by the process of vasculogenesis.2This process has been studied most extensively in the mouse yolk sac, wherein endothe-lial progenitors are specified in the mesoderm and induced to form an initial capillary plexus by effec-tors derived from the adjacent visceral endoderm, including vascular endothelial growth factor (VEGF), Indian hedgehog (Ihh), and bFGF. Specification of the early capillary plexus into arterial or venous fate occurs as the plexus goes on to remodel into a circu-latory network of branching vessels. Recent studies reviewed by Torres-Vazquez et al3provide evidence that distinct molecular differences between arterial and venous endothelial cells exist before blood vessel assembly and the onset of blood flow. Early arterial specification is regulated by complex molecular pathways involving VEGF, members of the Notch signaling pathway, and neuropilin-1 (VEGF164 -specific receptor). Specification of venous fate volves other distinct signaling pathways that in-clude neuropilin-2 and Tie2. Further downstream, demarcation of arterial-venous boundaries is estab-lished through the EphrinB/EphB signaling path-way, wherein EphrinB2 is distinctly expressed by arterial endothelial cells, and its receptor EphB4 is expressed in venous endothelium. Although endo-thelial cells demonstrate early specification to an ar-terial or venous fate, they can exhibit plasticity, and further patterning of arteries and veins is controlled by other factors such as blood flow. In a recent study using the chicken yolk sac as an experimental model to assess arterial-venous differentiation, purposeful disruption of arterial blood flow on one side of the yolk sac led to venous differentiation of vessels on that side, suggesting that flow is a major factor con-trolling arterial patterning.4 In addition, this study demonstrated that exogenous application of Eph-rinB2 and EphB4 in vivo to the allantois at a later, more mature stage of yolk sac vascular devel-opment induced the formation of arterial-venous
Accepted for publication Jan 20, 2005. doi:10.1542/peds.2005-0132 No conflict of interest declared.
Address correspondence to Josephine M. Enciso, MD, Department of Pedi-atrics, Texas Children’s Hospital, Feigin Center, 6621 Fannin, FC 530.01, Houston, TX 77030. E-mail: [email protected]
PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad-emy of Pediatrics.
shunts. These results suggest that these proteins may have a role in enhancing shear stress, leading to the induction of vascular shunts, which form as an ad-aptation to aberrations in flow-induced shear stress.5
VESSEL WALL RECRUITMENT
Stabilization and survival of endothelial tubes oc-curs with the recruitment of mural cells. This step also involves multiple signaling pathways including platelet-derived growth factor-B (PDGF-B) and its receptor PDGFR-, angiopoietin 1 and its receptor Tie2, and transforming growth factor -1 (TGF-1). Proliferating endothelial cells secrete PDGF-B which then interacts with its receptor PDGFR-on the sur-face of mural cell precursors and acts as a chemoat-tractant and mitogen for these cells.6Angiopoietin 1 is secreted by mural cells and, through its interac-tions with its receptor Tie2 on endothelial cells, sta-bilizes vessels by recruiting mural cells to the vessel wall and mediating interactions between mural cells and endothelial cells.7The importance of controlled activation of Tie2 is demonstrated by a mutation that leads to increased receptor activation, resulting in venous malformation characterized by dilated ve-nous channels and variable recruitment of smooth muscle cells.8 On contact with endothelial cells, newly recruited mesenchymal cell progenitors are induced toward a mural cell fate in a process medi-ated by the activation of TGF-1.6,9TGF--mediated mural cell differentiation also requires heterocellular communication between endothelial cells and mural cells via gap junction channels.10
In humans, TGF-signaling seems to play an impor-tant role in arteriovenous development. Mutations in 1 of 2 different genes within the TGF-receptor family of proteins, endoglin or activin-like receptor kinase-1 (ALK1), have been found to cause the autosomal dom-inant disorder hereditary hemorrhagic telangiectasia.11 This disorder is characterized by arteriovenous malfor-mations, telangiectasias, and mucosal and gastrointes-tinal bleeding. Although the precise mechanisms for the vascular abnormalities in hereditary hemorrhagic telangiectasia have not been elucidated, there are known roles for TGF1,12endoglin, and ALK1 in the control of endothelial proliferation and migration, as well as in the promotion of mural cell differentiation to form an intact vessel wall.
VASCULAR REMODELING
Remodeling of the primary capillary plexus into an extensive circulatory network of branching ves-sels involves tight regulation of ECM degradation by proteases in addition to endothelial and mural cell proliferation and migration. Degradation of the blood vessel basement membrane and ECM by pro-teases (urokinase plasminogen activator and MMPs such as MMP2, MMP3, and MMP9), balanced by protease inhibitors such as plasma activator inhibitor (PAI-1) and tissue inhibitors of MMPs (TIMPs), pro-motes directed endothelial and mural cell migration. The ECM also stores proangiogenic growth factors such as VEGF and bFGF, which are released by pro-teases from their ECM sites and promote endothelial cell proliferation.
A tightly controlled balance between ECM degra-dation and deposition is required for endothelial cell homeostasis. Multiple studies, in vitro and in vivo, have demonstrated that elevated MMP activity pro-motes tumor invasion, metastasis, and new vessel formation. Conversely, inhibition of MMP activity has been shown to have antiangiogenic effects via inhibition of proteolytic degradation of the ECM and specific cellular processes such as endothelial cell proliferation and migration.13,14 Thus, the modula-tion of MMP activity is critical for normal vascular remodeling and maturation.
Recent data from studies in mice have further elu-cidated the role of MMPs and their inhibitors in blood vessel formation during development. Mutant mice with inactivating mutations of individual MMPs such as MMP2, MMP9, and MT1-MMP dis-play normal embryonic development and have no obvious vascular defects, suggesting that MMPs may have redundant roles during early embryonic devel-opment. However, mice lacking both MMP2 and MT1-MMP die immediately postnatally as a result of respiratory failure and blood vessel abnormalities.15 Capillaries in the cerebral cortex, the diaphragm, and skeletal muscle of MMP2/MT1-MMP– deficient mice exhibit narrowed lumens compared with normal capillaries and were lined with abnormally large, rounded endothelial cells that were morphologically distinct from the flattened endothelium of normal capillaries. These findings demonstrate a role for MMP2 and MT1-MMP in postnatal blood vessel for-mation and suggest that the lack of these specific proteases may result in luminal narrowing second-ary to dysregulated ECM accumulation.
The importance of MMP inhibition and pericellu-lar regulation of MMP activity during vascupericellu-lar de-velopment is demonstrated by the dede-velopmental defects observed in mutant mice lacking the MMP inhibitor RECK.16Unlike other secreted MMP inhib-itors such as TIMP-1 and TIMP-2, RECK contains a glycophosphatidyl inositol-anchoring transmem-brane domain that anchors it to the cell memtransmem-brane. Membrane localization concentrates RECK on the plasma membrane, allowing local pericellular regu-lation of ECM proteolysis. RECK inhibits 3 MMP family members: MMP-2, MMP-9, and MT1-MMP. Unlike embryos deficient in TIMP-1 and TIMP-2, which develop normally, embryos lacking RECK die at embryonic day 10.5, a stage at which vessel re-modeling and maturation normally occur. The vas-culature seen in both the embryo and yolk resembles a primary capillary plexus that lacks a hierarchical circulatory network of branching vessels. These find-ings suggest that vasculogenesis can occur in the absence of RECK; however, additional remodeling and stabilization of blood vessels requires regulated inhibition of MMP proteolytic activity. In these mu-tant embryos, differentiated smooth muscle cells, which express RECK, were recruited to vessel struc-tures, suggesting no effect of RECK deficiency on mural cell migration and differentiation. Destabiliza-tion of blood vessels was suspected to be caused by the excessive degradation of ECM components such as collagen I. Overall, these studies demonstrate that
COMMENTARIES 229
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regulation of MMP proteolytic activity is critical for vascular maturation and patterning.
SUMMARY
In their study, Marler et al1provide the first evi-dence that vascular tumors and malformations may be angiogenesis-dependent. The finding of increased levels of MMPs in the urine of patients with vascular lesions suggests dysregulated activity of MMPs, leading to increased ECM degradation, lack of endo-thelial cell proliferative control and migration, and destabilization of nascent blood vessel structures. Disruption of flow in unstable vessels could lead to lack of appropriate arterial-venous differentiation. Increased degradation of ECM also results in loss of endothelial cell homeostasis and can account for the defects observed in vascular tumors that exhibit un-controlled endothelial cell proliferation. In all, these findings provide a rationale for the potential use of MMP inhibitors in the treatment of congenital vas-cular anomalies.
Josephine M. Enciso, MD Department of Pediatrics
Karen K. Hirschi, PhD
Departments of Pediatrics and Molecular and Cellular Biology
Texas Children’s Hospital Baylor College of Medicine Houston, TX 77030
REFERENCES
1. Marler JJ, Fishman SJ, Kilroy SM, et al. Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies.Pediatrics.2005;116:38 – 45
2. Risau W. Mechanisms of angiogenesis.Nature.1997;386:671– 674 3. Torres-Vazquez J, Kamei M, Weinstein BM. Molecular distinction
be-tween arteries and veins.Cell Tissue Res.2003;314:43–59
4. le Noble F, Moyon D, Pardanaud L, et al. Flow regulates arterial-venous differentiation in the chick embryo yolk sac.Development.2004;131: 361–375
5. Hacking WJ, VanBavel E, Spaan JA. Shear stress is not sufficient to control growth of vascular networks: a model study.Am J Physiol.
1996;270(1 pt 2):H364 –H375
6. Hirschi KK, Rohovsky SA, D’Amore PA. PDGF, TGF-, and heterotypic cell-cell interactions mediate the recruitment and differentiation of 10T2/3 cells to a smooth muscle cell fate [published correction appears inJ Cell Biol. 1998;141:1287].J Cell Biol.1998;141:805– 814
7. Suri C, Jones PF, Patan S, et al. Requisite role of angiopoietin-1, a ligand for the Tie2 receptor, during embryonic angiogenesis.Cell.1996;87: 1171–1180
8. Vikkula M, Boon LM, Carraway KL 3rd, et al. Vascular dysmorphogen-esis caused by an activating mutation in the receptor tyrosine kinase TIE2.Cell.1996;87:1181–1190
9. Hungerford JE, Owens GK, Argraves WS, et al. Development of the aortic vessel wall as defined by vascular smooth muscle and extracel-lular matrix markers.Dev Biol.1996;178:375–392
10. Hirschi KK, Burt JM, Hirschi KD, et al. Gap junction communication mediates transforming growth factor-beta activation and endothelial-induced mural cell differentiation.Circ Res.2003;93:429 – 437 11. van den Driesche S, Mummery CL, Westermann CJ. Hereditary
hem-orrhagic telangiectasia: an update on transforming growth factor signaling in vasculogenesis and angiogenesis.Cardiovasc Res.2003;58: 20 –31
12. Bohnsack BL, Lai L, Dolle P, et al. Signaling hierarchy downstream of retinoic acid that independently regulates vascular remodeling and endothelial cell proliferation.Genes Dev.2004;18:1345–1358
13. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior.Annu Rev Cell Dev Biol.2001;17:463–516
14. Moses MA, Sudhalter J, Langer R. Identification of an inhibitor of neovascularization from cartilage.Science.1990;248:1408 –1410
15. Oh J, Takahashi R, Adachi E, et al. Mutations in two matrix metallo-proteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice.
Oncogene.2004;23:5041–5048
16. Oh J, Takahashi R, Kondo S, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis.Cell.2001;107:789 – 800
The Steroid Odyssey in Croup
S
teroids are not indicated in the management of croup; I still have the pre-PowerPoint slides that say so. I used them for my resident teaching sessions of 3 decades ago. Today’s slides (we need a better term for our electronically stored, digitized images that are projected directly as the need arises) herald the opposite, ie, steroids are the standard of care in the management of croup. Segal et al,1in this issue of Pediatrics, documented an 86% decrease in the number of hospital admissions for treatment of croup in Ontario, Canada, between 1993 and 2002. This change coincided with the adoption of outpa-tient glucocorticoid therapy for croup. Therefore, the observations by Segal et al1 can be viewed as out-come data supporting the efficacy of glucocorticoid therapy for this disease. This prompts a brief review of the steroid odyssey in croup.Perhaps the most notable early challenge of the anti-steroid dogma was Coffin’s oft-cited 1971 letter to the editor titled, “Corticosteroids in Croup: Is There a Reply From the Ivory Tower?”2 Previous clinical trials reported in influential journals did not support efficacy.3,4In 1979, the publication of a rea-sonably performed clinical trial demonstrating ben-efit from dexamethasone5 did not seem to tilt the ivory tower, as evidenced by an accompanying neg-ative editorial.6The turning point was the 1989 meta-analysis by Kairys et al,7which reviewed the 9 meth-odologically satisfactory trials (5 positive and 4 negative) of glucocorticoids in croup. The principal outcomes were clinical improvement at 12 and 24 hours and decreased rates of tracheal intubation. The investigators found improved odds ratios for all 3 of these criteria and a dose-response relationship for these outcomes. Kairys et al7 concluded that “this meta-analysis supports the practice of using steroids to treat patients ill enough to be hospitalized for croup.”
The next logical question was to ask whether glu-cocorticoids would benefit children with croup not ill enough to require hospitalization. Terry Klassen, who was destined to become the cutting-edge croup investigator who would change the treatment of chil-dren with mild/moderate disease, published the first study in 1994.8 In their randomized, clinical trial,
Accepted for publication Mar 23, 2005. doi:10.1542/peds.2005-0676
No conflict of interest declared.
Address correspondence to Milton Tenenbein, MD, Department of Pediat-rics, University of Manitoba, Children’s Hospital, 840 Sherbrook St, Win-nipeg, Manitoba, R3E 1S1, Canada. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad-emy of Pediatrics.
DOI: 10.1542/peds.2005-0132
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