2
recognition of ECM occurs through a variety of receptors including both integrin
and non-integrin adhesion receptors [34, 58, 89, 97], and these mediate the complex
signals that are delivered. There is considerable evidence that ECM can provide
both stimulatory and inhibitory signals [34, 89], and thus, the ECM composition,
the vascular cell types, and the biological context of the signaling dictate the cellular
response that occurs. An important regulator of ECM structure and function are
MMPs which can degrade matrix components [31, 33, 35, 47, 52] but can also
release liberate factors such as growth factors and cytokines from these matrices to
affect vascular cell behavior. Within the vascular wall, homotypic interactions
between ECs [37] and heterotypic interactions of ECs and mural cells affect ECM
production and deposition [92, 94], as well as its ability to be degraded by MMPs
[87]. Many new studies are now focused on such interactions to understand how
mural cells affect EC behavior during development and under various disease conditions [1, 5, 56, 92, 94]. In this chapter, we will review past and present work that
addresses mechanisms by which ECM, MMPs, small GTPase signaling, defined
growth factors, and EC-pericyte interactions influence vascular tube assembly and
remodeling, tube stabilization, and vascular regression to control tissue vascularization in normal versus disease states.
1.2 Concepts in Vascular Tube Morphogenesis in 3D
Extracellular Matrices
1.2.1 Extracellular Matrix and Vascular Morphogenesis
A critical regulator of vascular morphogenesis is the ECM which serves as a physical, mechanical, and agonistic substrate to affect survival, motility, invasion, and
morphogenic events of both endothelial cells (ECs) and mural cells, including pericytes and vascular smooth muscle cells [1, 18, 34–36, 58, 81, 89, 92]. Interestingly,
different types of ECM have distinct effects on the developing or mature vasculature, depending on the biologic context, with evidence for pro-morphogenic, prostabilization, or pro-regressive activities [31, 34, 35, 89]. Also, certain ECM
environments may present quiescence signals to vascular cells that play an important role in vascular stabilization. Alteration in the ECM, through proteolysis or
conformational changes, is known to generate matricryptic sites which activate
cells, and thus, the ECM is a critical regulator of how cells perceive their environment and sense an injurious stimulus [24, 26]. Furthermore, the ECM is a scaffold
that possesses adhesive signals for cells, by binding to both integrin and non- integrin
surface receptors, but it also binds and presents specific growth factors to cells [34,
57, 58, 89]. The ECM also modulates the activation of specific growth factors and,
thus, can modulate growth factor action to affect the vasculature [58]. It is clear that
co-signaling between integrins and growth factor receptors is a critical regulator of
vascularization events both during development and in postnatal life. The ECM is
G. E. Davis
recognition of ECM occurs through a variety of receptors including both integrin
and non-integrin adhesion receptors [34, 58, 89, 97], and these mediate the complex
signals that are delivered. There is considerable evidence that ECM can provide
both stimulatory and inhibitory signals [34, 89], and thus, the ECM composition,
the vascular cell types, and the biological context of the signaling dictate the cellular
response that occurs. An important regulator of ECM structure and function are
MMPs which can degrade matrix components [31, 33, 35, 47, 52] but can also
release liberate factors such as growth factors and cytokines from these matrices to
affect vascular cell behavior. Within the vascular wall, homotypic interactions
between ECs [37] and heterotypic interactions of ECs and mural cells affect ECM
production and deposition [92, 94], as well as its ability to be degraded by MMPs
[87]. Many new studies are now focused on such interactions to understand how
mural cells affect EC behavior during development and under various disease conditions [1, 5, 56, 92, 94]. In this chapter, we will review past and present work that
addresses mechanisms by which ECM, MMPs, small GTPase signaling, defined
growth factors, and EC-pericyte interactions influence vascular tube assembly and
remodeling, tube stabilization, and vascular regression to control tissue vascularization in normal versus disease states.
1.2 Concepts in Vascular Tube Morphogenesis in 3D
Extracellular Matrices
1.2.1 Extracellular Matrix and Vascular Morphogenesis
A critical regulator of vascular morphogenesis is the ECM which serves as a physical, mechanical, and agonistic substrate to affect survival, motility, invasion, and
morphogenic events of both endothelial cells (ECs) and mural cells, including pericytes and vascular smooth muscle cells [1, 18, 34–36, 58, 81, 89, 92]. Interestingly,
different types of ECM have distinct effects on the developing or mature vasculature, depending on the biologic context, with evidence for pro-morphogenic, prostabilization, or pro-regressive activities [31, 34, 35, 89]. Also, certain ECM
environments may present quiescence signals to vascular cells that play an important role in vascular stabilization. Alteration in the ECM, through proteolysis or
conformational changes, is known to generate matricryptic sites which activate
cells, and thus, the ECM is a critical regulator of how cells perceive their environment and sense an injurious stimulus [24, 26]. Furthermore, the ECM is a scaffold
that possesses adhesive signals for cells, by binding to both integrin and non- integrin
surface receptors, but it also binds and presents specific growth factors to cells [34,
57, 58, 89]. The ECM also modulates the activation of specific growth factors and,
thus, can modulate growth factor action to affect the vasculature [58]. It is clear that
co-signaling between integrins and growth factor receptors is a critical regulator of
vascularization events both during development and in postnatal life. The ECM is
G. E. Davis