ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 191

Fig. 4 Schematic diagram illustrating the contribution of TIMP-2 and -3 to pericyte-induced
vascular tube stabilization, as proposed in [ 77 ]. TIMP-2 is derived from ECs, whereas TIMP-3 is
produced by pericytes. Together, they contribute to vascular stabilization by inhibiting a variety
of MMPs, ADAMs, and VEGFR-2. The initiation of tube stabilization requires the blockade of
both EC tube formation and EC tube regression, which further leads to the cessation of EC
activation and the development of EC quiescence. Pericytes are required for ECs to assemble
basement membrane matrices, which may locally capture and present TIMP-3 to ECs through
heparan sulfate proteoglycans. (Figure reproduced from [ 77 ] with permission from The

Rockefeller University Press.)

and is then presented to the ECs via heparin sulfate proteoglycans in the basement
membrane, which suppress MT1-MMP activity and encourage sprouting of the
ECs (Fig. 4 )[ 77 , 78 ]. Furthermore, all EC interactions with associating pericytes
via Ang-1 or PDGF serve to inactivate and inhibit MT1-MMP after the basement
membrane has been reproduced and to ensure vascular quiescence.
C. A Disintegrin and metalloproteinase (ADAM)
ADAMs are a family of secreted and transmembrane proteins that control cell
adhesion, as well as proteolytic processing of the ectodomains of cell surface
receptors and signaling molecules [ 79 ]. Like previously described MMPs, ADAMs
have both pre- and propeptide domains, with the pro- domain acting as an
intramolecular chaperone that controls protein folding [ 80 ] and enzyme latency via
a cysteine-switch mechanism [ 81 , 82 ]. At this point, the structures differ, with
ADAMs having a disintegrin-like domain with a loop that is able to interact with
neighboring cell integrins [ 83 ]. Following this region, a cysteine-rich domain, then
an EGF-like domain, followed by a membrane-spanning region and a cytoplasmic
tail. The cytoplasmic domain is able to interact with proteins of intracellular