75
growth [43, 199]. In all of these situations, the tissue or vasculature is deprived of
oxygen, leading to hypoxic conditions that promote angiogenesis. For vessel
sprouting, the ECM surrounding the vasculature needs to be degraded so that ECs
can easily navigate into the tissue and proliferate. Hypoxia is known to promote
the production of ECM-degrading enzymes via secretion from activated ECs [21,
61, 65]. Thus, EC sprouting is more favorable toward hypoxic regions in the ECM
through which the secretion of enzymes is upregulated by hypoxia, whereas the
invasion of vessels into the ECM is not favored in the direction of sufficiently oxygenated regions.
An oxygen gradient emerges in early development, which guides cellular differentiation and morphogenesis [141]. While the O 2 uptake of early embryonic
cells relies on the simple diffusion of oxygen, hypoxia starts to be observed in
different regions as the embryo expands [5, 141]. The initial vascularization, vasculogenesis, starts with the differentiation of angioblasts (embryonic progenitors
of ECs), which surround hemopoietic cells to form blood islands. Blood islands
ultimately fuse as angioblasts differentiate into endothelial cells to form the primary capillary plexus and then undergo further tubulogenesis and vascular network formation throughout the yolk sac [156, 185, 230]. This process of
vasculogenesis has been suggested to occur in hypoxic conditions [141, 156].
Hypoxia also stimulates microvascularization and the capillary network to form
around the developing organs. Vasculogenesis in adult organs has been demonstrated to originate from endothelial progenitor cells (EPCs) circulating in the
blood [225]. The migration of EPCs and their recruitment to the appropriate sites
to induce the formation of new blood vessels depends on complex cell signaling.
Circulating EPCs home to hypoxic regions along both O 2 and growth factor gradients, in particular gradients of stromal-derived factor 1 (SDF-1) [33, 51].
Investigations of tumor growth and wound healing have revealed that hypoxia
occurs in both situations, inducing EPCs to migrate from the circulating blood
through the ECM. Hypoxia also plays a role in the recruitment of EPCs by promoting receptor expression on the tissue that recognizes EPCs [242], as well as
on the EPCs themselves [35], which is followed by their differentiation into
mature ECs [32]. Moreover, vascular endothelial growth factor (VEGF), a key
regulatory protein known to induce vasculogenesis and angiogenesis, was found
to be upregulated in hypoxia [159]. These processes take place in the milieu of the
ECM, which is mostly composed of fibronectin during early development [49,
148]. In adult tissue, on the other hand, collagen becomes abundant and controls
the cellular fate.
The formation of new blood vessels through angiogenesis or vasculogenesis
depends on the dynamic effects and interplay between the ECM and oxygen tension. A thorough understanding of the mechanisms involving the ECM and O 2 during angiogenesis and vasculogenesis is essential for the fundamental understanding
that can be harnessed for developing vascular engineering applications. Indeed, the
effects of these two factors on vascular cells are being investigated extensively. The
in vitro vascularization of primary vascular cells has been studied using many different biomaterials [10, 24, 88] as three-dimensional (3D) matrix components, and
4 Hypoxia and Matrix Manipulation for Vascular Engineering
growth [43, 199]. In all of these situations, the tissue or vasculature is deprived of
oxygen, leading to hypoxic conditions that promote angiogenesis. For vessel
sprouting, the ECM surrounding the vasculature needs to be degraded so that ECs
can easily navigate into the tissue and proliferate. Hypoxia is known to promote
the production of ECM-degrading enzymes via secretion from activated ECs [21,
61, 65]. Thus, EC sprouting is more favorable toward hypoxic regions in the ECM
through which the secretion of enzymes is upregulated by hypoxia, whereas the
invasion of vessels into the ECM is not favored in the direction of sufficiently oxygenated regions.
An oxygen gradient emerges in early development, which guides cellular differentiation and morphogenesis [141]. While the O 2 uptake of early embryonic
cells relies on the simple diffusion of oxygen, hypoxia starts to be observed in
different regions as the embryo expands [5, 141]. The initial vascularization, vasculogenesis, starts with the differentiation of angioblasts (embryonic progenitors
of ECs), which surround hemopoietic cells to form blood islands. Blood islands
ultimately fuse as angioblasts differentiate into endothelial cells to form the primary capillary plexus and then undergo further tubulogenesis and vascular network formation throughout the yolk sac [156, 185, 230]. This process of
vasculogenesis has been suggested to occur in hypoxic conditions [141, 156].
Hypoxia also stimulates microvascularization and the capillary network to form
around the developing organs. Vasculogenesis in adult organs has been demonstrated to originate from endothelial progenitor cells (EPCs) circulating in the
blood [225]. The migration of EPCs and their recruitment to the appropriate sites
to induce the formation of new blood vessels depends on complex cell signaling.
Circulating EPCs home to hypoxic regions along both O 2 and growth factor gradients, in particular gradients of stromal-derived factor 1 (SDF-1) [33, 51].
Investigations of tumor growth and wound healing have revealed that hypoxia
occurs in both situations, inducing EPCs to migrate from the circulating blood
through the ECM. Hypoxia also plays a role in the recruitment of EPCs by promoting receptor expression on the tissue that recognizes EPCs [242], as well as
on the EPCs themselves [35], which is followed by their differentiation into
mature ECs [32]. Moreover, vascular endothelial growth factor (VEGF), a key
regulatory protein known to induce vasculogenesis and angiogenesis, was found
to be upregulated in hypoxia [159]. These processes take place in the milieu of the
ECM, which is mostly composed of fibronectin during early development [49,
148]. In adult tissue, on the other hand, collagen becomes abundant and controls
the cellular fate.
The formation of new blood vessels through angiogenesis or vasculogenesis
depends on the dynamic effects and interplay between the ECM and oxygen tension. A thorough understanding of the mechanisms involving the ECM and O 2 during angiogenesis and vasculogenesis is essential for the fundamental understanding
that can be harnessed for developing vascular engineering applications. Indeed, the
effects of these two factors on vascular cells are being investigated extensively. The
in vitro vascularization of primary vascular cells has been studied using many different biomaterials [10, 24, 88] as three-dimensional (3D) matrix components, and
4 Hypoxia and Matrix Manipulation for Vascular Engineering