ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 188

with the surface of the ECs [ 49 ]. Despite significant differences in pathologic and
physiologic microenvironments, only small changes in soluble MMP expression
are observed [ 50 ]. For example, switching from a physiologic ECM containing
mostly collagen I to a provisional ECM comprised of fibrin, fibronectin, and
vitronectin typically found during wound healing or prolonged ischemic diseases,
results in slight modulation of the MMP expression profile [ 51 ].
Recent work suggests that there may be no single proteolytic mechanism
utilized by ECs to degrade the ECM. Instead several MMPs are likely used in
complement, and the specific combination and ratio of MMPs expressed and
utilized depends on the identity of the matrix as well as the identity of stromal cell
types that interact with the ECs. For example, when adipose-derived stem cells or
a generic fibroblast source were included as interstitial cells to induce capillary
sprouting in a fibrin matrix, the plasminogen activator-plasmin axis was the
preferred proteolytic mechanism utilized for capillary invasion into the matrix and
tubule lengthening, while MMPs appeared to play a distinct role regulating
capillary diameter and stabilization only. In contrast, when mesenchymal stem
cells from bone marrow were used in place of the adipose-derived cells,

MT-MMPs were the sole proteases for ECM invasion and sprouting [ 52 ].
Further work illustrating knockdown of either of the gelatinases, MMP-2 and
MMP-9, suggests that these two proteinases may work in concert to remodel the
ECM during angiogenic processes. When one of the two is targeted for gene
knockdown, sprouting is still able to occur. MMP-9 is unable to degrade type I
collagen alone, so thus it does not serve to encourage tunneling and sprouting of ECs
during angiogenesis via matrix proteolysis directly. Instead, its pro-angiogenic
capacity may lie in its ability to release bound VEGF (secreted by stromal cells)
from the matrix to induce sprouting. It is also capable of activating TGF-b, resulting
in promotion of tissue remodeling [ 53 , 54 ]. During in vivo wound healing and hind
limb ischemia studies, the peak activity levels of these MMPs coincide with gran-
ulation tissue formation, fibroblast migration into the tissue, and vascularization of
the wound [ 55 , 56 ]. Several research groups have now fabricated synthetic hydro-
gels with linkages sensitive to MMP-2 and MMP-9 so that cellular invasion can
occur in much the same way as in hydrogels of natural composition (e.g., collagen or
fibrin). In vitro studies using RGD-functionalized version of these MMP-sensitive
gels have demonstrated EC adhesion and capillary sprouting by mimicking key
elements found in natural matrix proteins [ 57 , 58 ]. Furthermore, tethering growth
factors such as VEGF to the matrix via proteolytically sensitive linkages recapit-
ulates the growth factor sequestration capacity of physiologic ECMs [ 59 ].
3. Anti-angiogenic roles of soluble MMPs
As mentioned previously, MMPs can be considered to be both pro- and anti-
angiogenic. MMP expression and activity can impede blood vessel formation via
one of two possible mechanisms. First, overactive MMPs can compromise ECM
stability, which may result in vascular regression. Second, MMP activity can
generate matrix fragments with anti-angiogenic capabilities.
With respect to the first possibility, the process of angiogenesis typically
culminates with vascular pruning. During this process, vessels that have not been