19
for tube remodeling events. In early vascular development, there is considerable
evidence for dramatic tube network remodeling that occurs following the onset of
flow [23, 72, 82], and we hypothesize that this is possible in large part due to the
presence of vascular guidance tunnels which allows ECs to rapidly rearrange to
accommodate the flows and pressure forces that are applied to the network. Also, at
this stage of development, the ECM is likely to be elastic, and, thus, the forces generated may be able to expand lumen or tunnel width by mechanical distension. We
have also shown that groups of cells comprising a tube structure can migrate together
through tunnel spaces, to move and connect with adjacent EC tubes to regulate such
vascular remodeling events [95]. As mentioned earlier, the EC lumen and tube formation process generates more vascular guidance tunnels than are utilized at any
given time, which further suggests that this occurs to accommodate the necessary
vascular remodeling events involved in generating a proper microcirculatory
network.
Vascular guidance tunnels are also important to consider in the context of vascular tube regression and regrowth of vessels. One of the ways to eliminate the possibility of vascular regrowth following regression events would be to induce regression
of both vascular tubes and vascular guidance tunnels. In fact, the MMP-1 and
MMP-10 regression mechanism discussed earlier does cause the collapse of both
structures. The presence of pericytes, which block the regression event, can thus
protect not only the vascular tube structure but also the integrity of the vascular
guidance tunnels. Of interest here is that tumor vessels are highly resistant to vascular regression, due to their production of regression inhibitors such as TIMP-1.
Again, TIMP-1 is capable of protecting both the vessels and the tunnel spaces. Also,
when tumors are treated with vascular regression agents, such as VEGF or VEGFR2
antagonists, vessels regress, but they can rapidly regrow (following withdrawal of
the regression agent), in a similar fashion, to recapitulate the original pattern of vessels [74]. This appears to occur through the vascular guidance tunnels that were
generated during initial tumor vessel formation. So an important therapeutic consideration here would be to devise approaches to induce vessel and vascular guidance
tunnel regression. In this way vessel regrowth is less likely to occur, allowing for a
better therapeutic opportunity to treat the tumors, their vascular supplies, and existing matrix conduits which facilitate vascular regrowth.
It is also important to consider how events such as arteriovenous identity might
be regulated by vascular guidance tunnels. The tunnels represent a 2D matrix surface in a 3D matrix environment [95]. There is important data showing that ephrinB2 (an arterial marker) and EphB4 (a venous marker) represent a repulsive
signaling pair, which appears early in development to control the development of
A-V identity [46]. These repulsive interactions allow differential cell sorting, and,
early in development, ECs expressing these markers are intermixed. Over time they
sort out and become segregated to either the arterial or venous side [46, 53, 65].
They also appear to sort very early, even at the level of initial cardinal vein formation, due to sprouting from the developing aorta. This process is very analogous to
what has been described for lymphatic sprouting and development from the cardinal
vein [103]. Notch signaling appears to control this phenomenon, and, when
1 Molecular Control of Capillary Tube Morphogenesis and Maturation Through…
for tube remodeling events. In early vascular development, there is considerable
evidence for dramatic tube network remodeling that occurs following the onset of
flow [23, 72, 82], and we hypothesize that this is possible in large part due to the
presence of vascular guidance tunnels which allows ECs to rapidly rearrange to
accommodate the flows and pressure forces that are applied to the network. Also, at
this stage of development, the ECM is likely to be elastic, and, thus, the forces generated may be able to expand lumen or tunnel width by mechanical distension. We
have also shown that groups of cells comprising a tube structure can migrate together
through tunnel spaces, to move and connect with adjacent EC tubes to regulate such
vascular remodeling events [95]. As mentioned earlier, the EC lumen and tube formation process generates more vascular guidance tunnels than are utilized at any
given time, which further suggests that this occurs to accommodate the necessary
vascular remodeling events involved in generating a proper microcirculatory
network.
Vascular guidance tunnels are also important to consider in the context of vascular tube regression and regrowth of vessels. One of the ways to eliminate the possibility of vascular regrowth following regression events would be to induce regression
of both vascular tubes and vascular guidance tunnels. In fact, the MMP-1 and
MMP-10 regression mechanism discussed earlier does cause the collapse of both
structures. The presence of pericytes, which block the regression event, can thus
protect not only the vascular tube structure but also the integrity of the vascular
guidance tunnels. Of interest here is that tumor vessels are highly resistant to vascular regression, due to their production of regression inhibitors such as TIMP-1.
Again, TIMP-1 is capable of protecting both the vessels and the tunnel spaces. Also,
when tumors are treated with vascular regression agents, such as VEGF or VEGFR2
antagonists, vessels regress, but they can rapidly regrow (following withdrawal of
the regression agent), in a similar fashion, to recapitulate the original pattern of vessels [74]. This appears to occur through the vascular guidance tunnels that were
generated during initial tumor vessel formation. So an important therapeutic consideration here would be to devise approaches to induce vessel and vascular guidance
tunnel regression. In this way vessel regrowth is less likely to occur, allowing for a
better therapeutic opportunity to treat the tumors, their vascular supplies, and existing matrix conduits which facilitate vascular regrowth.
It is also important to consider how events such as arteriovenous identity might
be regulated by vascular guidance tunnels. The tunnels represent a 2D matrix surface in a 3D matrix environment [95]. There is important data showing that ephrinB2 (an arterial marker) and EphB4 (a venous marker) represent a repulsive
signaling pair, which appears early in development to control the development of
A-V identity [46]. These repulsive interactions allow differential cell sorting, and,
early in development, ECs expressing these markers are intermixed. Over time they
sort out and become segregated to either the arterial or venous side [46, 53, 65].
They also appear to sort very early, even at the level of initial cardinal vein formation, due to sprouting from the developing aorta. This process is very analogous to
what has been described for lymphatic sprouting and development from the cardinal
vein [103]. Notch signaling appears to control this phenomenon, and, when
1 Molecular Control of Capillary Tube Morphogenesis and Maturation Through…