Vascular homeostasis: insights from a fibrotic mouse

delivery of cancer chemotherapeu-tic agents depends on the permeability of the tumor vasculature. The natural hyperper-meability of tumor vessels increases absorption of macromolecular drugs into tumor tissue, suggesting that further enhancement of this process could be beneficial to the treatment of cancer (Baban and Seymour, 1998). Numerous studies have demonstrated that collagen, the most abundant protein of the extracellular matrix, plays an important role in regulating vessel permeability (Brown et al., 2003; Loeffler et al., 2006). The mechanism by which this occurs, however, had not been shown. A recent study by Sounni et al. in Disease Models & Mechanisms identifies a pathway by which collagen maintains vascular integrity in the Cola1(I) r/r mouse model (Sounni et al., 2010). In these mice, the collagenase cleavage site within type I collagen is mutated (Liu et al., 1995), causing a compensatory increase in collagenolytic activity and hemodynamic perturbation (Sounni et al., 2010). The proposed model suggests that type I collagen is a crucial component of a regulatory loop that links protease breakdown of extracellular matrix components with vascular permeability. Sounni et al. identified matrix metallo-proteinase-14 (MMP14) as the crucial protease that is activated downstream of type I collagen. This supports the earlier observation that MMPs are involved in vascular permeability (Gade et al., 2009). To determine which MMP is required for vessel stability, Sounni et al. conducted a series of in vivo assays to assess vascular leakage in MMP-knockout mice (see figure 1B in Sounni et al., 2010). The enhanced steady-state leakage in MMP14-null mice implicated MMP14 as the metalloproteinase that is crucial for maintaining vascular stability in this model (see figure 1D in Sounni et al., 2010). In addition, Sounni et al. employed the Cola1(I) r/r mouse model to demonstrate the influence of increased collagen levels on MMP activity and vessel stability. As expected, the Cola1(I) r/r mouse displayed increased MMP activity and decreased vascular permeability (see figure 2A,B in Sounni et al., 2010). The broad-spectrum metalloproteinase inhibitor GM6001 rescued this phenotype. Although the authors interrogated the influence of the related met-alloproteinase MMP2 on their proposed mechanism, the potential off-target effects of GM6001 on other MMPs should also be considered. Use of MMP14-specific antibodies, which have recently become available (Devy et al., 2009), would serve to strengthen these data. However, the results strongly suggest that the overabundance of uncleaved collagen in the Cola1(I) r/r mouse induces hyperactivation of MMP14, which in turn …