ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 192

signaling importance, as well as to control trafficking of proteins (Fig. 2 ). ADAMs
are named such due to their original structural homology to the small proteins of
hemorrhagic snake venoms that were able to bind platelet integrin a 2b b 3a to block
platelet aggregation [ 84 ].
Because ADAMs are an active family of metalloproteinases, they are able to
cleave ECM proteins and cause degradation of the bulk ECM in a locale. One
example of this is ADAM-9, which is able to cleave laminin and promote invasion
[ 85 ]. Several studies have shown a connection between ADAM-10 and cleavage of
adhesion molecules such as VE-cadherin, where the ADAM is able to disassemble
the junctional contacts that control permeability and assist with encouragement of
EC migration and tubule sprouting [ 7 , 86 ]. Other ADAMs that are known to
control ECM degradation and release activators of ECs to a migratory phenotype
that will start the angiogenic cascade, are ADAMS-15 and -17 [ 7 ]. ADAMs are
also able to induce shedding of adhesion molecules such as PECAM-1, or their
activity may mobilize growth factors, chemokines, or other soluble factors that can
influence angiogenic processes [ 87 ].
D. Inhibitors of Matrix Metalloproteinases
Tissue inhibitors of metalloproteinases (TIMPs) are the main enodogenous
inhibitors of MMPs. There are four mammalian TIMPs that have been identified
and characterized within the literature. They are all known to regulate MMP
activity during periods of tissue remodeling, with molecular weights between 20
and 29 kDa [ 88 ]. All TIMPs inhibit MMP substrates in a 1:1 stoichiometric ratio
[ 89 ], with each TIMP binding the active site cleft in the catalytic domain of an
MMP, in the same manner as an ECM substrate would bind the MMP [ 40 ]. Each
TIMP has disulfide bonds of a three loop N-terminal domain, which is where
interaction with the catalytic domains of MMPs occurs, and a complementary
three loop C-subdomain [ 90 ].
All TIMPs are secreted proteins, but TIMPs-2, -3, and -4 can all be found near
the surface of a cell, in association with different MMPs [ 91 ]. All four TIMPs are
known to inhibit active forms of all MMPs; however, their inhibition abilities vary
widely. The main exception to this rule is that TIMP-1 is a poor inhibitor of MMP-
19, MT1-MMP, and MT3-MMP [ 92 ]. TIMP-3 easily inhibits many of the ADAMs
[ 93 ]. Examples of preferential binding are the ability of TIMP-1 to preferentially
bind with pro-MMP-9, and TIMP-2 preferentially binding with pro-MMP-2 to
inhibit conversion to active forms of these MMPs [ 94 , 95 ].
TIMP-2 has a special functional role in controlling the activation of pro-MMP-2,
with MT1-MMP also acting as a modulator. This activation step takes place on the
cell surface, thus the need for inclusion of MT1-MMP for activation [ 96 ]. According
to Strongin et al., the increased activation of MMP-2 in the presence of TIMP-2 is the
result of the N-terminal inhibitory domain of TIMP-2 binding to the active site of
MT1-MMP, and the C-terminal domain of TIMP-2 interacting with the C-terminal
hemopexin domain of pro-MMP-2 [ 97 ]. An additional unique feature of TIMP-2 is
its ability to suppress angiogenesis by reducing EC proliferation cues from bFGF via
its C-terminal region [ 98 ].