Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity

Abstract

Disruption of the thrombospondin 2 gene (Thbs2) in mice results in a complex phenotype characterized chief ly by abnormalities in fibroblasts, connective tissues, and blood vessels. Consideration of this phenotype suggested to us that the foreign body reaction (FBR) might be altered in thrombospondin 2 (TSP2)-null mice. To investigate the participation of TSP2 in the FBR, polydimethylsiloxane (PDMS) and oxidized PDMS (ox-PDMS) disks were implanted in TSP2-null and control mice. Growth of TSP2-null and control skin fibroblasts in vitro also was evaluated on both types of disks. Normal fibroblasts grew as a monolayer on both surfaces, but attachment of the cells to ox-PDMS was weak and sensitive to movement. TSP2-null fibroblasts grew as aggregates on both surfaces, and their attachment was further compromised on ox-PDMS. After a 4-week implantation period, both types of PDMS elicited a similar FBR with a collagenous capsule in both TSP2-null and control mice. However, strikingly, the collagenous capsule that formed in TSP2-null mice was highly vascularized and thicker than that formed in normal mice. In addition, abnormally shaped collagen fibers were observed in capsules from mutant mice. These observations indicate that the presence or absence of an extracellular matrix component, TSP2, can inf luence the nature of the FBR, in particular its vascularity. The expression of TSP2 therefore could represent a molecular target for local inhibitory measures when vascularization of the tissue surrounding an implanted device is desired.

Matricellular Proteins as Modulators of Cell–Matrix Interactions: Adhesive Defect in Thrombospondin 2-null Fibroblasts is a Consequence of Increased Levels of Matrix Metalloproteinase-2

“…Histological analysis of skin showed that collagen fibers are disorganized and lack the normal predominant parallel orientation to the epidermal surface, and examination of these fibers at the electron microscopic level revealed the presence of abnormally large collagen fibrils with irregular contours in tissues from mutant animals. Although the presence of TSP2 as a constituent of collagen fibers could not be documented in the developing or adult mouse (Kyriakides et al, 1998b), TSP2 was found to colocalize with collagen fibers in the tissue responses to injury that accompanied the foreign body reaction (Kyriakides et al, 1999a) and wound healing (Kyriakides et al, 1999b).…”

The Biocompatibility Manifesto: Biocompatibility for the Twenty-first Century

“…Plateletderived growth factor is an FDA-approved therapeutic for wound healing [10]. A study using knockout mice identified thrombospondin2 (TSP2) as a key regulator of the FBR [11]. By delivering antisense cDNA to block the production of TSP2, enhanced angiogenesis and a diffuse collagen deposition (in contrast to dense, highly aligned collagen in the expected capsule) were noted [12].…”

Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2

“…Further, ultrastructural studies demonstrated that TSP2 influences ECM assembly (15, 16). TSP2 KO mice displayed improved recovery of blood flow following ischemia (17), altered foreign body response (18,19), and accelerated wound healing (16,20,21). In contrast, TSP1 KO mice displayed delayed healing because of insufficient stimulation of inflammation (13).…”