ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 189

stabilized regress as some of the interstitial collagen is broken down. Specifically,
plasmin-mediated activation of MMPs-1, -10, and -13 has been shown to induce
vascular regression as each of these MMPs (although predominantly MMP-1) can
digest interstitial collagens [ 60 ]. This subset of MMPs, in conjunction with MMPs-
2, -9, and MT1-MMP, may act together to digest multiple different ECM
components based on these enzymes' specificities for different substrates [ 60 , 61 ].
The first subset breaks down native type I collagen, while the gelatinases more
efficiently degrade denatured collagens. A direct correlation between the levels of
active MMPs in maturing capillary beds and the levels of vascular regression has
been reported [ 62 , 63 ].
With respect to the second possibility, the proteolytic degradation products of
MMPs are anti-angiogenic. Proteolytic degradation of collagen IV, one of the
primary components of basement membrane, generates anti-angiogenic fragments
that include arrestin, canstatin, tumstatin, and metastatin [ 34 ]. MMP-9
predominantly produces free tumstatin, as well as smaller amounts of arresten and
canstatin. Other MMPs, including MMP-2, -3, and -13, are also able to liberate
tumstatin, although not as efficiently as MMP-9 [ 64 ]. Tumstatin targets the a V b 3
integrin, which is not expressed at measurable levels in physiologic angiogenesis,
but is seen at much higher levels in tumor angiogenesis. Studies have explored the
possibility of using tumstatin to reduce pathologic angiogenesis [ 64 ]. Arrestin,
another collagen IV breakdown fragment, binds the a 1 b 1 integrin receptor for
collagen I, and inhibits EC proliferation, as well as migration and further tube
formation in vitro. Similarly, collagen XVIII is a component of the interstitial
matrix beneath the basement membrane of the vasculature. Collagen XVIII
breakdown products are endostatin and neostatins, which are small, varying
molecular weight molecules that are the further breakdown products of endostatin.
MMPs-3, -7, -9, and -13, as well as MT1-MMP, act on collagen XVIII to produce
these fragments. Endostatin affects VEGF signaling, EC proliferation and
migration as well, in part by acting on the a 5 b 1 integrin [ 65 - 68 ]. Another unique
function of endostatin is its ability to inhibit MT1-MMP and MMP-2 activities [ 69 ].
B. Membrane-Type Matrix Metalloproteinases (MT-MMPs)
The membrane-type MMPs (MT-MMPs) represent another grouping of MMPs,
so named because they are bound to the cell's plasma membrane via either a
C-terminal transmembrane domain or a glycophosphatidyl inositol (GPI) anchor
[ 39 , 70 ]. Both classifications include a ''pre'' region, a propeptide region with a
furin-susceptible site, a catalytic domain, a hinge region, and a hemopexin domain.
After furin activation intracellularly, the proteinase gets processed and sent to the
cell membrane, where the catalytic, hinge, and hemopexin domains lie extracel-
lularly. These external regions are held at the cell surface by a transmembrane
region attached to a short amino acid tail residing in the cell cytoplasm, or a GPI
domain that is fixed in the cell membrane. These MT-MMPs provide spatial
control of matrix breakdown directly at the cell membrane surface [ 33 ].
MT-MMPs degrade gelatin, fibronectin, and aggrecan, as well as several other
ECM substrates [ 37 , 38 ].