76
they were shown to influence various aspects of angiogenesis and vasculogenesis.
Similarly, a considerable amount of work has focused on the effects of hypoxiainducible factors (HIF1α, HIF2α, HIF3α) on the regulation of genes that induce
vasculature network formation [68, 159, 241]. In addition, some researchers have
also investigated the effects of hypoxia and the ECM context together [170, 177].
Success in engineering blood vessels from primary vascular cells or stem cells relies
on understanding the influence of all critical parameters and controlling them in
targeted directions.
The main focus of this chapter is a review and discussion of how the cells in the
body respond to variations in oxygen tension and ECM components, leading to new
vasculature formation.
4.2 Concepts in the Regulation of the Vasculature by Oxygen
and the ECM
4.2.1 The Influence of Oxygen Tension on Vascularization
Variations in oxygen concentrations at every stage of embryogenesis and in different regions of adult tissues lead to diverse vascular responses, depending on the cell
type and microenvironment. Many cell types respond differently, but also collectively, to the changes in O 2 equilibrium through specialized sensing mechanisms
and effectors in order to maintain homeostasis. In this section, we will first discuss
the formation and location of poorly oxygenated regions in the body, as well as the
mechanisms that cells utilize to sense changes in oxygen levels. Then, we will then
focus on several responses of pluripotent and vascular cells to low O 2 tensions in
terms of gene regulation, differentiation, oxygen consumption, and cell survival.
4.2.1.1 The In Vivo Consequences of Oxygen Gradients
Oxygen Availability in the Body
In vertebrates, O 2 transport to the tissues relies on three main processes: the oxygenation of the blood in the alveoli in the lungs, the convectional transport of
oxygen in the blood along the veins, and the diffusion of oxygen across the vessel
walls followed by penetration of O 2 to the deeper tissues. There are three distinct
resistances to the mass transfer of the O 2 molecule, which result in O 2 gradients
throughout the body.
O 2 deprivation has been observed early in the development of mouse embryos
[141]. Additionally, polarographic oxygen measurements in the human placenta
have shown that O 2 levels are 1.3–3.5% in the first 8–10 weeks and reach between
7.2 and 9.5% in weeks 12–13 of pregnancy [188, 202]. Oxygen levels measured in
M. R. Blatchley et al.
they were shown to influence various aspects of angiogenesis and vasculogenesis.
Similarly, a considerable amount of work has focused on the effects of hypoxiainducible factors (HIF1α, HIF2α, HIF3α) on the regulation of genes that induce
vasculature network formation [68, 159, 241]. In addition, some researchers have
also investigated the effects of hypoxia and the ECM context together [170, 177].
Success in engineering blood vessels from primary vascular cells or stem cells relies
on understanding the influence of all critical parameters and controlling them in
targeted directions.
The main focus of this chapter is a review and discussion of how the cells in the
body respond to variations in oxygen tension and ECM components, leading to new
vasculature formation.
4.2 Concepts in the Regulation of the Vasculature by Oxygen
and the ECM
4.2.1 The Influence of Oxygen Tension on Vascularization
Variations in oxygen concentrations at every stage of embryogenesis and in different regions of adult tissues lead to diverse vascular responses, depending on the cell
type and microenvironment. Many cell types respond differently, but also collectively, to the changes in O 2 equilibrium through specialized sensing mechanisms
and effectors in order to maintain homeostasis. In this section, we will first discuss
the formation and location of poorly oxygenated regions in the body, as well as the
mechanisms that cells utilize to sense changes in oxygen levels. Then, we will then
focus on several responses of pluripotent and vascular cells to low O 2 tensions in
terms of gene regulation, differentiation, oxygen consumption, and cell survival.
4.2.1.1 The In Vivo Consequences of Oxygen Gradients
Oxygen Availability in the Body
In vertebrates, O 2 transport to the tissues relies on three main processes: the oxygenation of the blood in the alveoli in the lungs, the convectional transport of
oxygen in the blood along the veins, and the diffusion of oxygen across the vessel
walls followed by penetration of O 2 to the deeper tissues. There are three distinct
resistances to the mass transfer of the O 2 molecule, which result in O 2 gradients
throughout the body.
O 2 deprivation has been observed early in the development of mouse embryos
[141]. Additionally, polarographic oxygen measurements in the human placenta
have shown that O 2 levels are 1.3–3.5% in the first 8–10 weeks and reach between
7.2 and 9.5% in weeks 12–13 of pregnancy [188, 202]. Oxygen levels measured in
M. R. Blatchley et al.