Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1knockout mice cause reduced tumor vascularization

Integrin alpha 1 beta 1 is a collagen receptor abundantly expressed on micr ovascular endothelial cells. As well as being the only collagen receptor ab le to activate the Ras/Shc/mitogen-activated protein kinase pathway promoti ng fibroblast cell proliferation, it also acts to inhibit collagen and meta lloproteinase (MMP) synthesis. We have observed that in integrin alpha 1-nu ll mice synthesis of MMP7 and MMP9 was markedly increased compared with tha t of their wildtype counterparts. As MMP7 and MMP9 have been shown to gener ate angiostatin from circulating plasminogen, and angiostatin acts as a pot ent inhibitor of endothelial cell proliferation, we determined whether tumo r vascularization was altered in the alpha 1-null mice. Tumors implanted in to alpha 1-null mice showed markedly decreased vascularization, with a redu ction 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 circula ting plasminogen, In vitro analysis of alpha 1-null endothelial cells revea led a marked reduction of their proliferation on both integrin alpha 1-depe ndent (collagenous) and independent (noncollagenous) substrata. This reduct ion was prevented by culturing alpha 1-null cells with plasma derived from plasminogen-null animals, thus omitting the source from which to generate a ngiostatin. Plasma from tumor-bearing alpha 1-null animals uniquely inhibit ed endothelial cell growth, and this inhibition was relieved by the coaddit ion of either MMP inhibitors, or antibody to angiostatin, Integrin alpha 1- deficient mice thus provide a genetically characterized model for enhanced angiostatin production and serve to reveal an unwanted potential side effec t of MMP inhibition, increased tumor angiogenesis.