The histological effects of an intracranial arterial occlusion in the adult rat can be predicted on day 1 by the neurological score described in this report. Significant improvement can be obtained in these animals by reestablishing arterial flow 60 minutes or sooner after the ictus. The pattern of cortical pannecrosis observed after permanent occlusion (> or = 72 hours) was transformed into incomplete ischemic injury in most instances of transient occlusion.

Integrin ␣1␤1 is a collagen receptor abundantly expressed on microvascular endothelial cells. As well as being the only collagen receptor able to activate the Ras͞Shc͞mitogen-activated protein kinase pathway promoting fibroblast cell proliferation, it also acts to inhibit collagen and metalloproteinase (MMP) synthesis. We have observed that in integrin ␣1-null mice synthesis of MMP7 and MMP9 was markedly increased compared with that of their wildtype counterparts. As MMP7 and MMP9 have been shown to generate angiostatin from circulating plasminogen, and angiostatin acts as a potent inhibitor of endothelial cell proliferation, we determined whether tumor vascularization was altered in the ␣1-null mice. Tumors implanted into ␣1-null mice showed markedly decreased vascularization, with a reduction in capillary number and size, which was accompanied by an increase in plasma levels of angiostatin due to the action of MMP7 and MMP9 on circulating plasminogen. In vitro analysis of ␣1-null endothelial cells revealed a marked reduction of their proliferation on both integrin ␣1-dependent (collagenous) and independent (noncollagenous) substrata. This reduction was prevented by culturing ␣1-null cells with plasma derived from plasminogen-null animals, thus omitting the source from which to generate angiostatin. Plasma from tumor-bearing ␣1-null animals uniquely inhibited endothelial cell growth, and this inhibition was relieved by the coaddition of either MMP inhibitors, or antibody to angiostatin. Integrin ␣1-deficient mice thus provide a genetically characterized model for enhanced angiostatin production and serve to reveal an unwanted potential side effect of MMP inhibition, increased tumor angiogenesis.