ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 187

Propeptide
(with Cys switch) MMPs

Hinge region

Zn

C

Pre

Pro

Amino-terminal
catalytic domain
(Zn binding)

Carboxy-terminal
hemopexin-like
domain

Signal
sequence

Propeptide
(with Cys switch)

EGF
repeat

Disintegrin
domain

ADAMs

Cytoplasmic tail

Zn

C

Pre Pro

Signal
sequence

Amino-terminal
catalytic domain
(Zn binding)

Cysteine-rich
motif

Transmembrane
domain

Fig. 2 Schematic representation of the structures of MMPs and ADAMs. Both protease families
contained conserved features, a ''pre'' or signal sequence, a propeptide domain (pro) (with either
a cysteine switch or a furin-susceptible site), and a catalytic, Zn-binding domain. Additional
sequences in some MMPs include a hinge region (H) and hemopexin domain, and other features
not shown here. ADAMs contain a disintegrin domain, a cysteine-rich motif, an EGF repeat, a
transmembrane domain, and a cytoplasmic tail

ECM and hypoxic tissue [ 45 ]. Upon signaling to initiate sprouting, the tip cells
must first proteolyze the capillary basement membrane, which is primarily com-
prised of laminin, collagen IV, heparin-sulfate proteoglycans, and entactin [ 46 ].
Multiple MMPs can degrade these ECM components: MMP-2, MMP-3, MMP-7,
MMP-9, MMP-10, MMP-12, and MT1-MMP [ 33 ]. As mentioned previously, two
important growth factors in the initiation of the angiogenic cascade, VEGF and
bFGF, produce vesicles containing pro-MMP-2 and pro-MMP-9, as well as
MT1-MMP. Upregulation of these MMPs is thus associated with increased

basement membrane invasion abilities of ECs [ 47 ].
After the basement membrane has been broken down, ECs induce MMP
expression from interstitial cells by secreting extracellular matrix metallopro-
teinase inducer (EMMPRIN) [ 48 ]. The majority of MMP production may be from
these surrounding interstitial and inflammatory cells present in the matrix, rather
than the ECs forming the actual new capillary sprouts. Interstitial flow from the
vasculature to the lymphatics, which is enhanced following degradation of the
basement membrane barrier, combined with this increased MMP production,
creates chemotactic gradients that further encourage EC invasion into the ECM.
This is perhaps achieved by the interaction of various ECM breakdown products