on April 22, 2004
Published online before print April 22, 2004, doi: 10.1161/01.ATV.0000129537.72553.73
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Submitted on February 23, 2004
Accepted on April 14, 2004
Deep Vein Thrombosis Resolution Is Modulated by Monocyte CXCR2-Mediated Activity in a Mouse Model
Peter K. Henke *;
From the Section of Vascular Surgery, Jobst Vascular Research Laboratory, Department of Surgery (P.K.H., A.V., S.D., C.B.D., J.E., P.S., P.T., G.R.U., T.W.W.), the Division of Pulmonary Medicine, Department of Medicine (D.A.A.), and the Department of Pathology (S.L.K.), University of Michigan Medical School, Ann Arbor, Mich.
* To whom correspondence should be addressed. E-mail: henke{at}umich.edu.
Objective--To determine the role of CXCR2, the receptor for cysteine-X-cysteine (CXC) chemokines, and its primary effector cell, the neutrophil (PMN), on deep venous thrombosis (DVT) resolution.
Methods and Results--DVT in BALB/c, anti-CXCR2 antibody-treated, and BALB/c CXCR2-/- mice were created by infrarenal IVC ligation and the thrombus harvested at various time points over 21 days. The CXCR2-/- mice had significantly larger thrombi at early time points (days 2 to 8), and significantly decreased intrathrombus PMNs, monocytes, and neovascularization as compared with controls. Thrombus KC/CXCL1 was significantly higher at 2 days in CXCR2-/- thrombi as measured by enzyme-linked immunosorbent assay. Fibrin content was significantly higher, with less uPA gene expression at 4 days in CXCR2-/- thrombi. Late fibrotic maturation of the thrombus was delayed in the CXCR2-/- mice, with significantly decreased 8 day MMP-2 activity, whereas MMP-9 activity was elevated as compared with controls. Similar impairment in DVT resolution was found at 8 days with anti-CXCR2 inhibition. However, systemic neutropenia, unlike CXCR2 deletion, did not increase the thrombus size as compared with controls.
Conclusions--Normal DVT resolution involves CXCR2-mediated neovascularization, collagen turnover, and fibrinolysis, and it is probably primarily monocyte-dependent.
Key words: inflammation • chemokines • neutrophils • angiogenesis
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