ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 185

The final step in the angiogenic process, tube stabilization, coincides with the
production of laminin to form a new basement membrane along the basal surface
of the nascent tubules. Integrins a 6 b 1 and a 3 b 1 , which bind ECs to specific laminin
isoforms, are known indicators of capillary maturation [ 27 , 28 ]. The expression of
these integrins suppresses several signaling pathways, and trigger EC quiescence
[ 29 , 30 ]. The laminin-rich basement membrane also provides an interface with
which both ECs and stabilizing pericytes can interact [ 7 ].
3 Proteinases Involved in Angiogenesis
The ECM must be broken down and reformed for many processes throughout life,
including embryonic development, various morphogenic processes, cellular
reproduction, and tissue remodeling. The matrix itself serves as a platform for cell
growth and support, but is also capable of controlling cellular attachment,
proliferation, migration, and differentiation of cells via cell-ECM interactions.
Many cytokines and growth factors can also be sequestered in the matrix and
stored for later use. Several different types of angiogenic proteinases modulate the
ECM in varying ways to influence angiogenesis. Some proteases indirectly
promote EC proliferation, while others degrade the ECM to allow for tunneling
ECs to invade and form tubules. Others control growth factor release from the
matrix, altering cues that can direct or inhibit the angiogenic process. A final group
of proteinases also controls cell adhesion to the matrix, inducing polarity within
the blood vessels. These adhesions may direct cells to migrate, proliferate, or
remain quiescent, based on the levels of varying integrins expressed, and the
contents of the matrix to which they bind. MMPs are the main degradative
enzymes responsible for modulating the ECM in a tissue. They are always
contributing to the evolving matrix as it changes in different ways to support and
encourage various cellular processes. In addition to both membrane-bound and
soluble MMPs, ADAMs are another important group of proteins that influence
ECM remodeling. A final grouping of players is the tissue inhibitors of metallo-
proteinases (TIMPs), which can control angiogenesis and subsequent matrix
remodeling by maintaining vascular quiescence and halting angiogenic cues to
maintain the angiogenic switch in the ''off'' position.
A. Soluble Matrix Metalloproteinases
Secreted matrix metalloproteinases are a family of zinc-containing endopep-
tidases that are able to degrade various ECM components. They are produced as
pro-enzymes that are proteolytically processed to become activated. A sulfhydryl
group in the pro-domain of all MMPs, known as a ''cysteine switch,'' is able to
work in sync with the zinc ion of the catalytic site to maintain cell quiescence [ 31 ].
By disrupting this cysteine-zinc binding, the MMP takes the first step toward
activation [ 32 ].
In general, the naming scheme follows a simple numerical order, starting with
the first to be discovered, MMP-1, which acts on collagens. It was originally