74
metastasis. At the most basic level, two of the most critical components of the cellular microenvironment are oxygen (O 2 ) and the composition of the extracellular
matrix (ECM).
According to the most recent findings, O 2 reached sufficient levels (estimated to
be 0.2–2% O 2 ) for aerobic organisms to be able to survive between 2.45 and 2.2
billion years ago in the oceans [19, 154] and between 540 and 600 million years
ago in Earth’s atmosphere [72, 154, 194]. Ever since, O 2 has been a highly available potential source of energy for multicellular organisms to commence, survive,
and multiply. Multicellular organisms require specialized systems to enable sufficient amounts of O 2 to reach their cells. For instance, insects regulate the transport
of O 2 into their tissues with a special respiratory system consisting of spiracles and
trachea. Around their tissues, they retain the relatively low O 2 levels (1.4 mmHg)
thought to be equivalent to the atmospheric O 2 concentrations at the time of their
evolution [161, 162]. In vertebrates, O 2 is carried by proteins in the blood, particularly by hemoglobin, and is transported to tissues through endothelial cells (ECs).
The cells throughout the body are highly dependent on the dynamics of O 2 . In
humans, O 2 concentrations vary between 1 and 10% in tissues (other than the
lungs) and between 5 and 13% in blood vessels [126, 155]. Therefore, the ability
for cells to sense and respond to O 2 is critical, and O 2 acts as a signaling molecule
for cells, regulating their metabolism, survival, cell-cell interactions, migration,
and differentiation.
Besides O 2 availability, the transition from unicellular to multicellular organisms
requires that cells be connected together in a way that allows them to interact with
each other as parts of the same system. This interconnectedness could happen either
by having junctions at the cell peripheries or by having connecting cement between
the cells. Many multicellular organisms connect their cells in both ways: they use
cellular junctions to allow direct signaling between cells, and they use the ECM to
regulate the transport of molecules (e.g., O 2 , glucose, and signaling proteins)
between the cells by remodeling the components of the ECM. Thus, both cell-cell
and cell-ECM interactions are significant for determining the fate of cells in tissues.
Transmembrane proteins known as integrins are responsible for signaling from the
ECM to the cell. Therefore, cells have different responses with respect to the composition and structure of the surrounding ECM. In particular, vascular morphogenesis is regulated by endothelial cell (EC) interactions with the ECM through
integrins and is highly dependent on the ECM context [49].
In the field of vascular engineering, the effects of both O 2 tension and the ECM
on blood vessel formation continue to be extensively investigated. Blood vessel
formation essentially occurs by angiogenesis or vasculogenesis. Angiogenesis is
the formation of blood vessels from pre-existing vasculature, orchestrated with the
proliferation, migration, and assembly of ECs, as well as the remodeling of the
ECM [127, 213]. Most of the ECs comprising the blood vessel walls are in a state
of quiescence in physiological conditions. A stimulus is required for ECs to switch
from their resting state to their navigating state, where they are activated to produce angiogenesis-promoting proteins [70]. Angiogenesis occurs in several situations, such as wound healing, arthritis, cardiovascular ischemia, and solid tumor
M. R. Blatchley et al.
metastasis. At the most basic level, two of the most critical components of the cellular microenvironment are oxygen (O 2 ) and the composition of the extracellular
matrix (ECM).
According to the most recent findings, O 2 reached sufficient levels (estimated to
be 0.2–2% O 2 ) for aerobic organisms to be able to survive between 2.45 and 2.2
billion years ago in the oceans [19, 154] and between 540 and 600 million years
ago in Earth’s atmosphere [72, 154, 194]. Ever since, O 2 has been a highly available potential source of energy for multicellular organisms to commence, survive,
and multiply. Multicellular organisms require specialized systems to enable sufficient amounts of O 2 to reach their cells. For instance, insects regulate the transport
of O 2 into their tissues with a special respiratory system consisting of spiracles and
trachea. Around their tissues, they retain the relatively low O 2 levels (1.4 mmHg)
thought to be equivalent to the atmospheric O 2 concentrations at the time of their
evolution [161, 162]. In vertebrates, O 2 is carried by proteins in the blood, particularly by hemoglobin, and is transported to tissues through endothelial cells (ECs).
The cells throughout the body are highly dependent on the dynamics of O 2 . In
humans, O 2 concentrations vary between 1 and 10% in tissues (other than the
lungs) and between 5 and 13% in blood vessels [126, 155]. Therefore, the ability
for cells to sense and respond to O 2 is critical, and O 2 acts as a signaling molecule
for cells, regulating their metabolism, survival, cell-cell interactions, migration,
and differentiation.
Besides O 2 availability, the transition from unicellular to multicellular organisms
requires that cells be connected together in a way that allows them to interact with
each other as parts of the same system. This interconnectedness could happen either
by having junctions at the cell peripheries or by having connecting cement between
the cells. Many multicellular organisms connect their cells in both ways: they use
cellular junctions to allow direct signaling between cells, and they use the ECM to
regulate the transport of molecules (e.g., O 2 , glucose, and signaling proteins)
between the cells by remodeling the components of the ECM. Thus, both cell-cell
and cell-ECM interactions are significant for determining the fate of cells in tissues.
Transmembrane proteins known as integrins are responsible for signaling from the
ECM to the cell. Therefore, cells have different responses with respect to the composition and structure of the surrounding ECM. In particular, vascular morphogenesis is regulated by endothelial cell (EC) interactions with the ECM through
integrins and is highly dependent on the ECM context [49].
In the field of vascular engineering, the effects of both O 2 tension and the ECM
on blood vessel formation continue to be extensively investigated. Blood vessel
formation essentially occurs by angiogenesis or vasculogenesis. Angiogenesis is
the formation of blood vessels from pre-existing vasculature, orchestrated with the
proliferation, migration, and assembly of ECs, as well as the remodeling of the
ECM [127, 213]. Most of the ECs comprising the blood vessel walls are in a state
of quiescence in physiological conditions. A stimulus is required for ECs to switch
from their resting state to their navigating state, where they are activated to produce angiogenesis-promoting proteins [70]. Angiogenesis occurs in several situations, such as wound healing, arthritis, cardiovascular ischemia, and solid tumor
M. R. Blatchley et al.