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J Thorac Cardiovasc Surg 2005;129:773-781
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Osteopontin expression and adventitial angiogenesis induced by local vascular endothelial growth factor 165 reduces experimental aortic calcification

^a Department of Surgery, Division of Pediatric Cardiovascular Thoracic Surgery, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Ill
^b Department of Georg August University, GÖttingen, Germany
^c Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill

Received for publication May 14, 2004; revisions received June 21, 2004; accepted for publication June 28, 2004.

^_* Address for reprints: Ralf G. Seipelt, MD, Department of Thoracic and Cardiovascular Surgery, Georg August University, University Hospital, Robert-Koch Str 40, 37075 GÖttingen, Germany (E-mail: rseipelt{at}med.uni-goettingen.de).

BACKGROUND: Vascular calcification is a common pathologic and precisely regulated process involving bone-associated proteins such as osteopontin. In this study, we investigated mechanisms by which recombinant human vascular endothelial growth factor 165 protects the arterial wall from severe vascular remodeling, including calcification, a newly discovered biologic action of vascular endothelial growth factor.

METHODS: In a rabbit model of thoracic aortic end-to-end anastomosis that simulates cardiovascular intervention, recombinant human vascular endothelial growth factor 165 at a dose of 0.75 µg (n = 19) or albumin (control; n = 19) was delivered intraluminally and on the serosal surface. Animals were killed, and aortic tissue was evaluated by Western blotting, immunohistochemistry, and immunofluorescence at 4, 8, and 24 hours; 1 week; and 1 month after surgery.

RESULTS: All controls revealed extensive aortic medial calcification at 1 month, whereas calcification was significantly reduced or absent with vascular endothelial growth factor treatment. Compared with controls, vascular endothelial growth factor treatment resulted in an earlier infiltration of macrophages in the vessel media (at 8 hours: 5.7 ± 2.3 macrophages per high-power field in control vs 32.1 ± 7.5 in vascular endothelial growth factor-treated aortas; P < .001), whereas controls showed an increase in macrophages starting at 1 week (24.1 ± 6.9 vs 4.3 ± 1.8; P < .001). Osteopontin expression was transiently increased and detected in macrophages and endothelial cells in vascular endothelial growth factor-treated vessels, and adventitial microvascular density was significantly increased by 1 week (9.5 ± 0.43 vs 25.0 ± 1.3; P < .001).

CONCLUSIONS: Our data suggest that exogenous vascular endothelial growth factor is capable of increasing adventitial angiogenesis and shifting macrophage infiltration and osteopontin expression in the media to an earlier time point, thereby promoting prompt repair and diminishing vascular remodeling and calcification after acute vascular injury.

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