3
also mechanosensitive and responds to mechanical forces generated by cells that
exert tensional forces on this matrix. A key mechanosensitive ECM component is
fibronectin which contains matricryptic sites that affect self-assembly reactions,
particularly through the III-I domain [45, 77, 99, 106]. Interestingly, this domain is
exposed in instances where fibronectin is absorbed into surfaces, such as cell surfaces or ECM [24, 26, 99], and appears to be particularly exposed when cells exert
mechanical force on fibronectin through integrin-based interactions [106]. This
facilitates fibronectin binding to itself which promotes the self-assembly reaction
(i.e., including disulfide exchange to form covalent bonds between fibronectin molecules) necessary to form an insoluble matrix [77]. Since fibronectin is one of the
few ECM proteins with clear mechanosensitive domains, it suggests that fibronectin
may play a particularly important role in ECM assembly events that depend on
mechanical forces, such as those observed during vascular morphogenic events in a
variety of contexts [18, 94, 107].
1.2.2 Differential Effects of ECM Components on Vascular
Tube Morphogenesis
Certain ECM components are potent stimulators of vascular tube morphogenesis,
while others appear inhibitory. Interestingly, collagen type I, the most abundant
ECM component in adult animals, is a potent stimulator of vascular tube morphogenesis in 3D matrices [34, 100] (Fig. 1.1). An accumulating view is that fibrillar
collagen matrices are potent ECM agonists for these events. Another strong ECM
agonist for EC tube morphogenesis is fibrin [78, 91], a provisional matrix component that is deposited along with fibronectin during tissue injury [34]. Interestingly,
the collagen-binding integrins, α2β1 and α1β1, have been shown to control EC tube
morphogenic events in vitro and in vivo in collagenous matrices [9, 28, 34, 88],
while the fibrin-/fibronectin-binding integrins, αvβ3 and α5β1, have been shown to
control tube morphogenesis in fibrin matrices [9, 11]. Because of the strong promorphogenic influence of collagen and fibrin matrices, these have predominantly
been used to establish 3D EC tube morphogenic models [68, 78] that have strongly
enhanced our knowledge concerning the molecular basis for EC tubulogenesis,
sprouting, and tube maturation events. Overall, the ECM and integrin data strongly
suggests that vascular tube morphogenesis is connected to integrin-mediated recognition of different pro-morphogenic ECM components and that multiple members
of the integrin family can participate in stimulating EC tubulogenesis in 3D matrix
environments [27, 34]. It does not appear that any particular integrin family member
is special in its ability to affect tube morphogenesis. Their influence is dictated by
the ECM environment in which the morphogenic process takes place. In contrast, it
appears that laminin-rich matrices are likely to present inhibitory signals to endothelial cells to interfere with morphogenic events [34, 35, 71]. As blood vessels
mature, laminin matrix deposits as a component of the vascular basement
1 Molecular Control of Capillary Tube Morphogenesis and Maturation Through…
also mechanosensitive and responds to mechanical forces generated by cells that
exert tensional forces on this matrix. A key mechanosensitive ECM component is
fibronectin which contains matricryptic sites that affect self-assembly reactions,
particularly through the III-I domain [45, 77, 99, 106]. Interestingly, this domain is
exposed in instances where fibronectin is absorbed into surfaces, such as cell surfaces or ECM [24, 26, 99], and appears to be particularly exposed when cells exert
mechanical force on fibronectin through integrin-based interactions [106]. This
facilitates fibronectin binding to itself which promotes the self-assembly reaction
(i.e., including disulfide exchange to form covalent bonds between fibronectin molecules) necessary to form an insoluble matrix [77]. Since fibronectin is one of the
few ECM proteins with clear mechanosensitive domains, it suggests that fibronectin
may play a particularly important role in ECM assembly events that depend on
mechanical forces, such as those observed during vascular morphogenic events in a
variety of contexts [18, 94, 107].
1.2.2 Differential Effects of ECM Components on Vascular
Tube Morphogenesis
Certain ECM components are potent stimulators of vascular tube morphogenesis,
while others appear inhibitory. Interestingly, collagen type I, the most abundant
ECM component in adult animals, is a potent stimulator of vascular tube morphogenesis in 3D matrices [34, 100] (Fig. 1.1). An accumulating view is that fibrillar
collagen matrices are potent ECM agonists for these events. Another strong ECM
agonist for EC tube morphogenesis is fibrin [78, 91], a provisional matrix component that is deposited along with fibronectin during tissue injury [34]. Interestingly,
the collagen-binding integrins, α2β1 and α1β1, have been shown to control EC tube
morphogenic events in vitro and in vivo in collagenous matrices [9, 28, 34, 88],
while the fibrin-/fibronectin-binding integrins, αvβ3 and α5β1, have been shown to
control tube morphogenesis in fibrin matrices [9, 11]. Because of the strong promorphogenic influence of collagen and fibrin matrices, these have predominantly
been used to establish 3D EC tube morphogenic models [68, 78] that have strongly
enhanced our knowledge concerning the molecular basis for EC tubulogenesis,
sprouting, and tube maturation events. Overall, the ECM and integrin data strongly
suggests that vascular tube morphogenesis is connected to integrin-mediated recognition of different pro-morphogenic ECM components and that multiple members
of the integrin family can participate in stimulating EC tubulogenesis in 3D matrix
environments [27, 34]. It does not appear that any particular integrin family member
is special in its ability to affect tube morphogenesis. Their influence is dictated by
the ECM environment in which the morphogenic process takes place. In contrast, it
appears that laminin-rich matrices are likely to present inhibitory signals to endothelial cells to interfere with morphogenic events [34, 35, 71]. As blood vessels
mature, laminin matrix deposits as a component of the vascular basement
1 Molecular Control of Capillary Tube Morphogenesis and Maturation Through…