20
overactive Notch4 is produced in ECs, venous ECs inappropriately express ephrinB2, contributing to the development of arteriovenous malformations [65]. Of
great interest is that many of these lesions will regress following withdrawal of the
overactive Notch4. The important point to be made is that the repulsive ephrinB2EphB4 interactions are occurring within vascular guidance tunnels (formed as a
result of EC tube assembly), and the ability to sort following such interactions
requires the ECs to move around on 2D matrices at the vessel wall surface. These
interactions are secondary to ECs contacting each other.
However, the concept of vascular guidance tunnels extends to recruitment and
sorting of mural cells within the vessel wall as well. EphrinB2 is expressed on vascular smooth muscle cells, with selectivity in arteries so similar repulsive interactions are likely to control this cell distribution as well [41]. What is interesting here
is that this type of interaction would require that mural cell recruitment, to EC-lined
tubes and within vascular tunnel spaces, occur in a polarized fashion exclusively on
the EC abluminal surface. In fact, we have recently discovered that this is precisely
what occurs during pericyte recruitment to EC-lined tubes. Within vascular guidance tunnels, they recruit to, and are localized only on, the EC tube abluminal surface [94]. Thus, mural cells could sort through repulsive interactions with each
other but also secondary to repulsive interactions with ECs. The vascular guidance
tunnel matrix conduit is a critical ECM structure necessary for these EC-EC, mural
cell- mural cell, and EC-mural cell interactions to occur and to also allow the motility events required for proper sorting. In support of this possibility is that ECs and
mural cells are highly dynamic during vascular tube assembly, and in fact, we have
shown that both ECs and pericytes rapidly migrate in the ECM, as well as within
vascular guidance tunnels during tube co-assembly and maturation events [94].
ECs have also been shown by a number of groups to be rapidly migrating in vivo
during vascular development, to regulate both tube assembly and vascular remodeling [23, 72].
1.3.12 Pericyte Recruitment to Vascular Guidance Tunnels
Induces Vascular Tube Stabilization
Many studies indicate that microvessels covered with pericytes are more stable to
pro-regressive stimuli but also show reduced vascular permeability indicative of
tube stabilization. Different vascular beds have varying pericyte numbers covering
capillary networks, although many have approximately 20–25% coverage of pericytes relative to ECs. Individual pericytes can span across multiple ECs, resembling
other types of supporting cells such as glia in the nervous system interacting with
multiple neurons. Tissues such as the central nervous system, including the retina,
have a very high pericyte to EC ratio which approaches 1:1. Thus, these interactions
account in part for the blood-brain barrier with strongly increased permeability barrier functions relative to other vascular beds. Considerable work suggests that the
G. E. Davis
overactive Notch4 is produced in ECs, venous ECs inappropriately express ephrinB2, contributing to the development of arteriovenous malformations [65]. Of
great interest is that many of these lesions will regress following withdrawal of the
overactive Notch4. The important point to be made is that the repulsive ephrinB2EphB4 interactions are occurring within vascular guidance tunnels (formed as a
result of EC tube assembly), and the ability to sort following such interactions
requires the ECs to move around on 2D matrices at the vessel wall surface. These
interactions are secondary to ECs contacting each other.
However, the concept of vascular guidance tunnels extends to recruitment and
sorting of mural cells within the vessel wall as well. EphrinB2 is expressed on vascular smooth muscle cells, with selectivity in arteries so similar repulsive interactions are likely to control this cell distribution as well [41]. What is interesting here
is that this type of interaction would require that mural cell recruitment, to EC-lined
tubes and within vascular tunnel spaces, occur in a polarized fashion exclusively on
the EC abluminal surface. In fact, we have recently discovered that this is precisely
what occurs during pericyte recruitment to EC-lined tubes. Within vascular guidance tunnels, they recruit to, and are localized only on, the EC tube abluminal surface [94]. Thus, mural cells could sort through repulsive interactions with each
other but also secondary to repulsive interactions with ECs. The vascular guidance
tunnel matrix conduit is a critical ECM structure necessary for these EC-EC, mural
cell- mural cell, and EC-mural cell interactions to occur and to also allow the motility events required for proper sorting. In support of this possibility is that ECs and
mural cells are highly dynamic during vascular tube assembly, and in fact, we have
shown that both ECs and pericytes rapidly migrate in the ECM, as well as within
vascular guidance tunnels during tube co-assembly and maturation events [94].
ECs have also been shown by a number of groups to be rapidly migrating in vivo
during vascular development, to regulate both tube assembly and vascular remodeling [23, 72].
1.3.12 Pericyte Recruitment to Vascular Guidance Tunnels
Induces Vascular Tube Stabilization
Many studies indicate that microvessels covered with pericytes are more stable to
pro-regressive stimuli but also show reduced vascular permeability indicative of
tube stabilization. Different vascular beds have varying pericyte numbers covering
capillary networks, although many have approximately 20–25% coverage of pericytes relative to ECs. Individual pericytes can span across multiple ECs, resembling
other types of supporting cells such as glia in the nervous system interacting with
multiple neurons. Tissues such as the central nervous system, including the retina,
have a very high pericyte to EC ratio which approaches 1:1. Thus, these interactions
account in part for the blood-brain barrier with strongly increased permeability barrier functions relative to other vascular beds. Considerable work suggests that the
G. E. Davis