ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 184

receptors [ 6 - 8 ]. Integrins, in turn, can regulate EC proliferation, survival, and the
formation of functional vessel lumens [ 8 - 11 ]. If the ECs fail to adhere to the ECM,
proliferation ceases and angiogenesis thus also stops [ 7 , 12 - 15 ].
At the earliest stages of angiogenesis, the basement membrane, consisting
primarily of laminin-1 and type IV collagen, gets degraded to expose the ECs to
the surrounding interstitial matrix [ 16 ]. In a quiescent state, the basement
membrane helps insulate the ECs from this interstitial matrix and inhibits EC
invasion and migration [ 7 ]. Following its degradation, a gradient of ECM
components and the cytokines attached to them provide a set of cues to direct EC
motility. In wound healing, for example, the interstitial matrix consists primarily
of fibrin and type I collagen, and supports subsequent EC migration and sprouting
[ 17 ]. VEGF plays a particularly critical role at this stage, as it is known to induce
a 1 b 1 and a 2 b 1 integrin expression, both of which bind type I collagen. Type I
collagen also helps to transform the leading ECs into a tip cell phenotype [ 18 ]. One
mechanism known to disrupt angiogenesis for therapeutic or alternative purposes
is to disrupt the formation of the collagen triple helix via alteration of the prolines.
This results in a cessation of collagen recognition and binding by the ECs,
effectively halting angiogenic invasion and tubule formation [ 19 ].
Once a nascent tubule escapes the basement membrane and begins to invade the
interstitial matrix, extension of the capillary sprout begins. Type I collagen induces
nascent cord formation and a migratory EC phenotype in part by suppressing
cyclic AMP, which causes increased actin polymerization and stress fiber
formation within the EC cytoskeleton [ 7 ]. This enables the ECs to generate
substantial contractile forces and apply tension to the matrix over relatively large
distances, which in turn supports capillary cord formation along the matrix fibers.
Other cell types do not migrate and produce cords when implanted in fibrin or
collagen gels in the same way [ 20 ]. Disruption of vascular endothelial cadherin
(VE-cadherin) intercellular junctions via signaling mechanisms induced by
collagen I binding also help to induce initial sprouting of ECs from a base vessel
[ 16 ]. Disrupted of their quiescent cell-cell contacts, ECs begin to migrate and
develop into nascent cords [ 19 , 21 ].
The next steps in the angiogenic process include the formation of hollow
lumens, followed by maturation of the nascent vessels. As mentioned previously
mentioned, integrin-mediated interactions between ECs and collagen, fibrin, and
fibronectin provide key instructive signals [ 22 - 24 ]. a 2 b 1 and a 1 b 1 are known
collagen receptors, while a V b 3 and a 5 b 1 are known fibronectin receptors that also
permit EC interactions with fibrin. Lumen formation is dependent on the formation
of these integrin-dependent intracellular vacuoles that are initially formed by the
process of pinocytosis, or in which small vesicles formation form to create pockets
within the cell. These vacuoles fuse together by exocytosis between adjacent ECs
and start to direct an apical-basal organization and polarization [ 25 , 26 ]. This
polarization requires membrane type-MMP (MT-MMP) to interact with the ECM
at the exterior of the newly formed lumens. The roles of these MT-MMPs will be
discussed in greater detail later in this chapter.