PEDIATRICS Vol. 116 No. 1 July 2005, pp. 228-230 (doi:10.1542/peds.2005-0132)
COMMENTARY |
Understanding Abnormalities in Vascular Specification and Remodeling
Department of Pediatrics
Departments of Pediatrics and Molecular and Cellular Biology
Texas Children’s Hospital
Baylor College of Medicine
Houston, TX 77030
Abbreviations: MMP, matrix metalloproteinase • bFGF, basic fibroblast growth factor • ECM, extracellular matrix • VEGF, vascular endothelial growth factor • TGF, transforming growth factor • TIMPs, tissue inhibitors of matrix metalloproteinase
Accurate classification, diagnosis, management, 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 of Pediatrics, Marler et al1 report novel findings that elevated levels of angiogenesis-related proteins, specifically high molecular 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 developed to characterize aggressive vascular malformations and tumors and provide additional evidence that antiangiogenic agents may be useful for the treatment of these lesions.
To approach diagnosis and management of congenital vascular lesions rationally, an understanding of the basic cellular, molecular, and genetic mechanisms of blood vessel formation is required. Recent advances in the field of vascular biology have contributed 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) differentiation, cell proliferation and migration, and the specification of arterial, venous, and lymphatic fate. Dysregulation of these processes can result in vascular malformations affecting 1 or multiple vascular types including capillary, arterial, venous, lymphatic, or arteriovenous channels.
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BLOOD VESSEL FORMATION |
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 TOP BLOOD VESSEL FORMATION VESSEL WALL RECRUITMENTVASCULAR REMODELINGSUMMARYREFERENCES |
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During embryonic development, blood vessels form de novo from endothelial progenitors by the process of vasculogenesis.2 This process has been studied most extensively in the mouse yolk sac, wherein endothelial progenitors are specified in the mesoderm and induced to form an initial capillary plexus by effectors 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 circulatory network of branching vessels. Recent studies reviewed by Torres-Vazquez et al3 provide 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 involves other distinct signaling pathways that include neuropilin-2 and Tie2. Further downstream, demarcation of arterial-venous boundaries is established through the EphrinB/EphB signaling pathway, wherein EphrinB2 is distinctly expressed by arterial endothelial cells, and its receptor EphB4 is expressed in venous endothelium. Although endothelial cells demonstrate early specification to an arterial 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 controlling arterial patterning.4 In addition, this study demonstrated that exogenous application of EphrinB2 and EphB4 in vivo to the allantois at a later, more mature stage of yolk sac vascular development induced the formation of arterial-venousshunts. 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 adaptation to aberrations in flow-induced shear stress.5
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VESSEL WALL RECRUITMENT |
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TOPBLOOD VESSEL FORMATIONVESSEL WALL RECRUITMENTVASCULAR REMODELINGSUMMARYREFERENCES |
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Stabilization and survival of endothelial tubes occurs 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-ß, angiopoietin 1 and its receptor Tie2, and transforming growth factor ß-1 (TGF-ß1). Proliferating endothelial cells secrete PDGF-B which then interacts with its receptor PDGFR-ß on the surface of mural cell precursors and acts as a chemoattractant and mitogen for these cells.6 Angiopoietin 1 is secreted by mural cells and, through its interactions with its receptor Tie2 on endothelial cells, stabilizes vessels by recruiting mural cells to the vessel wall and mediating interactions between mural cells and endothelial cells.7 The importance of controlled activation of Tie2 is demonstrated by a mutation that leads to increased receptor activation, resulting in venous malformation characterized by dilated venous 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 mediated by the activation of TGF-ß1.6,9 TGF-ß-mediated mural cell differentiation also requires heterocellular communication between endothelial cells and mural cells via gap junction channels.10
In humans, TGF-ß signaling seems to play an important role in arteriovenous development. Mutations in 1 of 2 different genes within the TGF-ß receptor family of proteins, endoglin or activin-like receptor kinase-1 (ALK1), have been found to cause the autosomal dominant disorder hereditary hemorrhagic telangiectasia.11 This disorder is characterized by arteriovenous malformations, telangiectasias, and mucosal and gastrointestinal bleeding. Although the precise mechanisms for the vascular abnormalities in hereditary hemorrhagic telangiectasia have not been elucidated, there are known roles for TGFß1,12 endoglin, 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.
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VASCULAR REMODELING |
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TOPBLOOD VESSEL FORMATIONVESSEL WALL RECRUITMENTVASCULAR REMODELINGSUMMARYREFERENCES |
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Remodeling of the primary capillary plexus into an extensive circulatory network of branching vessels 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 proteases (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), promotes directed endothelial and mural cell migration. The ECM also stores proangiogenic growth factors such as VEGF and bFGF, which are released by proteases from their ECM sites and promote endothelial cell proliferation.
A tightly controlled balance between ECM degradation and deposition is required for endothelial cell homeostasis. Multiple studies, in vitro and in vivo, have demonstrated that elevated MMP activity promotes 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 modulation of MMP activity is critical for normal vascular remodeling and maturation.
Recent data from studies in mice have further elucidated 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 display normal embryonic development and have no obvious vascular defects, suggesting that MMPs may have redundant roles during early embryonic development. 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 formation and suggest that the lack of these specific proteases may result in luminal narrowing secondary to dysregulated ECM accumulation.
The importance of MMP inhibition and pericellular regulation of MMP activity during vascular development is demonstrated by the developmental defects observed in mutant mice lacking the MMP inhibitor RECK.16 Unlike other secreted MMP inhibitors such as TIMP-1 and TIMP-2, RECK contains a glycophosphatidyl inositol-anchoring transmembrane domain that anchors it to the cell membrane. Membrane localization concentrates RECK on the plasma membrane, allowing local pericellular regulation 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 remodeling and maturation normally occur. The vasculature seen in both the embryo and yolk resembles a primary capillary plexus that lacks a hierarchical circulatory network of branching vessels. These findings 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 mutant embryos, differentiated smooth muscle cells, which express RECK, were recruited to vessel structures, suggesting no effect of RECK deficiency on mural cell migration and differentiation. Destabilization of blood vessels was suspected to be caused by the excessive degradation of ECM components such as collagen I. Overall, these studies demonstrate that regulation of MMP proteolytic activity is critical for vascular maturation and patterning.
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SUMMARY |
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TOPBLOOD VESSEL FORMATIONVESSEL WALL RECRUITMENTVASCULAR REMODELINGSUMMARYREFERENCES |
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In their study, Marler et al1 provide the first evidence 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 endothelial 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 uncontrolled endothelial cell proliferation. In all, these findings provide a rationale for the potential use of MMP inhibitors in the treatment of congenital vascular anomalies.
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FOOTNOTES |
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Accepted Jan 20, 2005.
Address correspondence to Josephine M. Enciso, MD, Department of Pediatrics, Texas Children’s Hospital, Feigin Center, 6621 Fannin, FC 530.01, Houston, TX 77030. E-mail: jenciso{at}bcm.edu
No conflict of interest declared.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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