ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 186

discovered when collagen gels were degraded by tadpole fin explants. The rest of
the MMPs are divided into subgroups based on domain structure and substrate
specificities: matrilysins (MMP-7 and MMP-26), collagenases (MMP-1, MMP-8,
MMP-13, and MMP-18), stromelysins (MMP-3, MMP-10, and MMP-11),
gelatinases (MMP-2 and MMP-9), enamelysins (MMP-20) and epilysins (MMP-
28), and others that don't fit into one of these subgroups (MMP-19, MMP-21,
MMP-22, MMP-23, and MMP-27) [ 33 - 35 ]. MMPs can also be classified based on
the basic domain groups that are included in their structures. All MMPs have three
common structural domains: the ''pre'' or signal sequence, the pro-peptide domain,
and the catalytically active domain (Fig. 2 ). MMPs-7 and -26 contain only these 3
domains, have a broad range of substrate specificity, and are able to degrade many
ECM proteins [ 36 - 38 ]. Addition of a hemopexin domain connected to the core
region via a proline-rich hinge region at the catalytic domain allows for enhanced
substrate specificity over those containing only the three basic regions. This hinge
region is also responsible for binding the family of specific MMP inhibitors
(TIMPs). Some examples of hemopexin-domain containing MMPs are collagen-
ases, which degrade the native helix of fibrillar collagens such as types I, II, and
III, as well as stromelysin-1 and -2, enamelysin, metalloelastase, and MMPs-19,
-22, and -27, which again don't fit into a specific structural class of MMPs [ 33 ].
These stromelysins, with their hemopexin domains, still have a rather broad
substrate specificity, degrading several groups of ECM proteins, including prote-
oglycans, fibronectin, and laminin [ 32 ]. Another similar grouping is the gelatinases
(MMPs-2 and -9) containing three head-to-tail cysteine-rich fibronectin type II-
like repeats within the catalytic domain [ 36 , 39 ]. These MMPs also degrade types
IV, V, VII, and X native collagens, as well as denatured collagen (gelatin),
fibronectin, and laminin [ 39 ]. When the cysteine-rich repeats are instead furin-
susceptible sites, stromelysin-3 and epilysin are classified as a grouping. Finally,
there are two outlying MMPs, including MMP-21, which does not have a hinge
region at all, and instead contains a vitronectin-like region within the propeptide
region, and MMP-23, which also lacks the hemopexin domain, containing a cys-
teine and proline-rich region followed by an immunoglobulin-imitating region [ 40 ].
Soluble MMPs can have both pro- and anti-angiogenic roles. Their pro-
angiogenic capacity is perhaps more obvious, given their ability to degrade ECM
components and jumpstart the path toward angiogenesis. Many growth factors and
cytokines are known to upregulate EC basement membrane degradation, as well as
EC proliferation, migration, and differentiation into a pro-angiogenic phenotype.
Examples of these molecules are VEGF, bFGF, and several interleukins, which
increase the amounts of inactive [ 41 ] and active[ 42 ] MMP-2 and MMP-9 [ 43 ].
However, because certain ECM cleavage products have anti-angiogenic proper-
ties, MMPs may also be considered anti-angiogenic as well [ 44 ].
1. Pro-angiogenic roles of soluble MMPs
During basement membrane degradation, a subgroup of ECs, known as ''tip
cells'', initiate sprouting. These cells possess high proteolytic activity, enabling
them to successfully break down the matrix and tunnel through the interstitial