ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 194

Fig. 5 A simplified schematic of the current concepts depicting the roles and regulation of
MMPs as they pertain to matrix remodeling. Figure reproduced from [ 140 ] with permission from
The American Physiological Society.)
provide physical space for the EC-pericyte interactions to take place. Stratman
et al. showed that the pericytes are recruited to the ablumenal surface and are able
to move along the EC tubules through these pre-formed spaces to regulate tubule
maturation and vascular basement membrane assembly [ 109 , 110 ]. Basement
membrane is deposited between ECs and pericytes within these tunnel voids.
Further work by this group showed that PDGF-BB and HB-EGF are necessary for
pericytes to accumulate within these tunnels and along EC tubules, and also for
proper basement membrane deposition. Without these growth factors directing the
behavior of the pericyte-EC interactions, their data suggest that no basement
membrane will be laid down [ 111 ]. This growth factor-pericyte interplay is known
to be regulated by MT1-MMP. Active MT1-MMP directly controls the binding to
PDGF receptor-B of pericytes after PDGF- b secretion by ECs. This cascade of
events then controls pericyte migration to sites of need along the vasculature, as
well as proliferation to induce greater vasculature stabilization and angiogenic
quiescence [ 71 , 73 ]. VEGF, an important initial cue for increased vessel
permeability followed by basement membrane degradation and EC sprouting, also
affects pericyte coverage. Treatment with VEGF antagonists results in increased
pericyte coverage and improved microcirculatory function with lower permeability
[ 112 , 113 ].
The TIE-2 receptor of ECs on the stalks of sprouting capillaries is a signaling
receptor that results in collagen IV expression throughout the stalk but not in the
tip cells of capillary sprouts. It is thought to be regulated by Ang-1 in the presence
of vascular smooth muscle cells (vSMCs) [ 45 ]. When vSMCs are absent, the
distinction between stalk and tip cells is eliminated, and MT1-MMP is expressed
throughout the structure [ 45 ]. Pericytes in co-cultures with ECs also express