Matrix metalloproteinases and angiogenesis

Angiogenesis is a prominent feature of numerous diseases, including cancer and arthritis, and appears to play an important role in kidney disease and hypertension. The matrix metalloproteinases, especially matrix metalloproteinase-2, play a vital role during angiogenesis by degrading the surrounding extracellular matrix and allowing endothelial cell invasion. Membrane type 1 matrix metalloproteinase directly degrades matrix components as well as activating matrix metalloproteinase-2 on the cell surface. The integrin receptors, particularly alphanubeta(3), can recruit and possibly activate matrix metalloproteinases to localized microdomains on the cell membrane. This restricts matrix metalloproteinase activity to the pericellular region, preventing excessive matrix degradation which would otherwise impede endothelial invasion. Inhibitors of matrix metalloproteinase activity may actually promote cell invasion by preventing uncontrolled matrix degradation. In addition to degrading the matrix, matrix metalloproteinases produce protein fragments that impede their angiogenic action. These multiple regulatory pathways permit fine control over cell invasion during angiogenesis and provide new, precise strategies for targeting abnormal angiogenesis, through control of matrix metalloproteinase activity.