Published online July 1, 2005
PEDIATRICS Vol. 116 No. 1 July 2005, pp. 38-45 (doi:10.1542/peds.2004-1518)
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Increased Expression of Urinary Matrix Metalloproteinases Parallels the Extent and Activity of Vascular Anomalies

Jennifer J. Marler, MD*,{ddagger}, Steven J. Fishman, MD*,{ddagger}, Susan M. Kilroy, BS{ddagger}, Jianmin Fang, PhD{ddagger}, Joseph Upton, MD*,{ddagger}, John B. Mulliken, MD*,{ddagger}, Patricia E. Burrows, MD*,§, David Zurakowski, PhD{ddagger}, Judah Folkman, MD*,{ddagger} and Marsha A. Moses, PhD{ddagger}

* Vascular Anomalies Center and Departments of
{ddagger} Surgery
§ Radiology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts

Objective. Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion.

Methods. A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician.

Results. Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF.

Conclusions. Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.

Key Words: vascular anomalies • matrix metalloproteinases • urinalysis

Abbreviations: CM, capillary malformation • LM, lymphatic malformation • VM, venous malformation • AVM, arteriovenous malformation • CLVM, capillary-lymphaticovenous malformation • ECM, extracellular matrix • MMP, matrix metalloproteinase • hMW, high molecular weight • bFGF, basic fibroblast growth factor • VEGF, vascular endothelial growth factor • CH, congenital hemangioma • IH, infantile hemangioma • ON, other endothelial neoplasms • COMBM, combined malformations • lMW, low molecular weight • OR, odds ratio • CI, confidence interval • PCH, pulmonary capillary hemangiomatosis • NGAL, neutrophil gelatinase–associated lipocalin

Accepted Oct 21, 2004.




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