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J Thorac Cardiovasc Surg 2005;130:355-362
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Local delivery of osteopontin attenuates vascular remodeling by altering matrix metalloproteinase-2 in a rabbit model of aortic injury

^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 Thoracic and Cardiovascular Surgery, Georg August University, Göttingen, Germany
^c Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill

Received for publication October 21, 2004; revisions received December 6, 2004; accepted for publication December 17, 2004.

^_* Address for reprints: Carl L. Backer, Division of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Children’s Memorial Hospital, 2300 Children’s Plaza, M/C 22, Chicago, IL 60614 (Email: cbacker{at}childrensmemorial.org).

OBJECTIVE: Vascular remodeling, often accelerated after cardiovascular procedures, may result in stenosis or aneurysm formation. The bone-associated protein osteopontin has been suggested to be involved in vascular remodeling, yet the effect of locally applied osteopontin in an acute vascular injury model of aortic calcification has not been examined.

METHODS: Vascular healing of rabbit thoracic aortas treated locally with recombinant osteopontin (dose: 1 µg; n = 16) or albumin (control, n = 16) after acute injury created by end-to-end anastomosis was evaluated. Matrix metalloproteinase-2 level was quantified by gelatin zymography. Proliferation of smooth muscle cells was detected by immunostaining for proliferative cell nuclear antigen.

RESULTS: Osteopontin-treated aortas showed significantly diminished vascular remodeling with less calcification (P = .001) and reduced anastomotic luminal stenosis (4% vs 28%, P = .002) compared with controls 2 months postsurgery. Moreover, osteopontin-treated aortas revealed a thickened adventitia with increased fibrosis (P = .006). Matrix metalloproteinase-2 level was up-regulated 2-fold with osteopontin treatment compared with control at 1 week, returning to baseline by 1 month. Staining for proliferation cell nuclear antigen disclosed an increase in proliferation cell nuclear antigen-positive smooth muscle cells in the media of osteopontin-treated aortas at 1 week, normalizing by 1 month.

CONCLUSIONS: These data suggest a beneficial effect of locally applied osteopontin after acute injury possibly by altering matrix metalloproteinase-2 activity and smooth muscle cell proliferation. Brief application of osteopontin may effectively enhance vascular healing by reducing calcification and thus maintaining luminal integrity. The role of the osteopontin-related increase in adventitial fibrosis on vascular healing has to be explored.

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