Integrin alpha1beta1 is a
collagen receptor abundantly expressed on microvascular endothelial cells. As well as being the only
collagen receptor able to activate the Ras/Shc/
mitogen-activated protein kinase pathway promoting fibroblast cell proliferation, it also acts to inhibit
collagen and
metalloproteinase (
MMP) synthesis. We have observed that in
integrin alpha1-null mice synthesis of MMP7 and MMP9 was markedly increased compared with that of their wild-type 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 alpha1-null mice.
Tumors implanted into alpha1-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 alpha1-null endothelial cells revealed a marked reduction of their proliferation on both
integrin alpha1-dependent (collagenous) and independent (noncollagenous) substrata. This reduction was prevented by culturing alpha1-null cells with plasma derived from
plasminogen-null animals, thus omitting the source from which to generate
angiostatin. Plasma from
tumor-bearing alpha1-null animals uniquely inhibited endothelial cell growth, and this inhibition was relieved by the coaddition of either
MMP inhibitors, or antibody to
angiostatin.
Integrin alpha1-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.