87
embryo consists of multiple components, culturing ECs on combinatorial ECM
arrays revealed optimal conditions for EC survival, in response to low O 2 and low
nutrient availability [104], as well as enhancements in EC fate which were regulated
by ECM composition, at least partially through upregulation of integrin β3 and its
associated signaling pathway [105].
In contrast, the adult ECM consists mostly of a laminin-rich basement membrane, which maintains the integrity of the mature endothelium, and interstitial collagen I, which promotes capillary morphogenesis [50]. Although collagen I is
present during development, its role becomes increasingly important in postnatal
angiogenesis, after its reactive groups have been cross-linked to further stabilize the
interstitial matrix [186]. EC integrins, which interact with collagens and fibrin, are
key receptors in EC activation, proliferation, and tubular morphogenesis. The
collagen- I-mediated activation of Src and Rho and the suppression of PKA promote
the formation of prominent actin stress fibers, which mediate EC retraction and
capillary morphogenesis. Moreover, the activation of Src also disrupts VE-cadherin
from cell junction and cell-cell contact which, in turn, facilitates multicellular reorganization. Conversely, basement membrane laminin-1 is responsible for maintaining the mature endothelium. During the proliferative stage of morphogenesis, the
laminin-rich basal lamina is degraded, exposing the tips of sprouting ECs to the
underlying interstitial collagens and activating signaling pathways that drive cytoskeletal reorganization and vascular morphogenesis. This sharp difference in how
ECM components affect capillary morphogenesis is responsible for controlling the
delicate balance between vascular sprouting and maturation.
Once nascent vessels are formed, ECM components regulate their maturation
and specialization into capillaries, arteries, and veins. Capillaries, the most abundant vessels in our body, consist of ECs surrounded by pericytes and basement
membrane. Exchanges of nutrients and oxygen occur through diffusion between
blood and tissue in these regions, due to the capillary’s thin wall structure and large
surface-area-to-volume-ratio. Maturation of the vessel wall involves the recruitment
of mural cells, development of the surrounding matrix, and organ-specific specialization [113]. ECM distribution in various tissues dictates the specialization of these
capillaries to support the functions of specific organs. The capillary endothelial
layer is continuous in most tissues (e.g., muscle), while it is fenestrated in exocrine
and endocrine glands (e.g., kidney and pancreas). Moreover, the enlarged sinusoidal
capillaries of the liver, spleen, and BM are discontinuous, allowing increased
exchange of hormones and metabolites between the blood and the surrounding tissues. In contrast, where the excess exchange of molecules is not desirable, such as
at the blood-brain barrier and the blood-retina barrier, the interendothelial connection is further reinforced with tight junctions, such as occludin and ZO-1 [238].
Compared with capillaries, arterioles and venules have an increased coverage of
mural cells and ECM components. Arterioles are completely surrounded with vascular SMCs that form a closely packed basement membrane. The walls of larger
vessels are composed of three layers: the tunica intima, the tunica media, and the
tunica adventitia. The EC layer of blood vessels is anchored to a basement membrane, which is the major component of the tunica intima [57]. The basement mem4 Hypoxia and Matrix Manipulation for Vascular Engineering
embryo consists of multiple components, culturing ECs on combinatorial ECM
arrays revealed optimal conditions for EC survival, in response to low O 2 and low
nutrient availability [104], as well as enhancements in EC fate which were regulated
by ECM composition, at least partially through upregulation of integrin β3 and its
associated signaling pathway [105].
In contrast, the adult ECM consists mostly of a laminin-rich basement membrane, which maintains the integrity of the mature endothelium, and interstitial collagen I, which promotes capillary morphogenesis [50]. Although collagen I is
present during development, its role becomes increasingly important in postnatal
angiogenesis, after its reactive groups have been cross-linked to further stabilize the
interstitial matrix [186]. EC integrins, which interact with collagens and fibrin, are
key receptors in EC activation, proliferation, and tubular morphogenesis. The
collagen- I-mediated activation of Src and Rho and the suppression of PKA promote
the formation of prominent actin stress fibers, which mediate EC retraction and
capillary morphogenesis. Moreover, the activation of Src also disrupts VE-cadherin
from cell junction and cell-cell contact which, in turn, facilitates multicellular reorganization. Conversely, basement membrane laminin-1 is responsible for maintaining the mature endothelium. During the proliferative stage of morphogenesis, the
laminin-rich basal lamina is degraded, exposing the tips of sprouting ECs to the
underlying interstitial collagens and activating signaling pathways that drive cytoskeletal reorganization and vascular morphogenesis. This sharp difference in how
ECM components affect capillary morphogenesis is responsible for controlling the
delicate balance between vascular sprouting and maturation.
Once nascent vessels are formed, ECM components regulate their maturation
and specialization into capillaries, arteries, and veins. Capillaries, the most abundant vessels in our body, consist of ECs surrounded by pericytes and basement
membrane. Exchanges of nutrients and oxygen occur through diffusion between
blood and tissue in these regions, due to the capillary’s thin wall structure and large
surface-area-to-volume-ratio. Maturation of the vessel wall involves the recruitment
of mural cells, development of the surrounding matrix, and organ-specific specialization [113]. ECM distribution in various tissues dictates the specialization of these
capillaries to support the functions of specific organs. The capillary endothelial
layer is continuous in most tissues (e.g., muscle), while it is fenestrated in exocrine
and endocrine glands (e.g., kidney and pancreas). Moreover, the enlarged sinusoidal
capillaries of the liver, spleen, and BM are discontinuous, allowing increased
exchange of hormones and metabolites between the blood and the surrounding tissues. In contrast, where the excess exchange of molecules is not desirable, such as
at the blood-brain barrier and the blood-retina barrier, the interendothelial connection is further reinforced with tight junctions, such as occludin and ZO-1 [238].
Compared with capillaries, arterioles and venules have an increased coverage of
mural cells and ECM components. Arterioles are completely surrounded with vascular SMCs that form a closely packed basement membrane. The walls of larger
vessels are composed of three layers: the tunica intima, the tunica media, and the
tunica adventitia. The EC layer of blood vessels is anchored to a basement membrane, which is the major component of the tunica intima [57]. The basement mem4 Hypoxia and Matrix Manipulation for Vascular Engineering