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.

Sea urchin skeletons are strengthened by flexible collagenous ligaments that bind together rigid calcite plates at sutures. Whole skeletons without ligaments (removed by bleaching) broke at lower apically applied forces than did intact, fresh skeletons. In addition, in three-point bending tests on excised plate combinations, sutural ligaments strengthened sutures but not plates. The degree of sutural strengthening by ligaments depended on sutural position; in tensile tests, ambital and adapical sutures were strengthened more than adoral sutures. Adapical sutures, which grow fastest, were also the loosest, suggesting that strengthening by ligaments is associated with growth. In fed, growing urchins, sutures overall were looser than in unfed urchins. Looseness was demonstrated visually and by vibration analysis: bleached skeletons of unfed urchins rang at characteristic frequencies, indicating that sound traveled across tightly fitting sutures; skeletons of fed urchins damped vibrations, indicating loss of vibrational energy across looser sutures. Furthermore, bleached skeletons of fed urchins broke at lower apically applied forces than bleached skeletons of unfed urchins, indicating that the sutures of fed urchins had been held together relatively loosely by sutural ligaments. Thus, the apparently rigid dome-like skeleton of urchins sometimes transforms into a flexible, jointed membrane as sutures loosen and become flexible during growth.

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