79
strated that, during the burn wound-healing process, the accumulation of HIF1α
increases the number of circulating angiogenic cells, as well as smooth muscle actinpositive cells, in the wounded tissue. These hypoxic conditions—either directly or
indirectly through the accumulation of HIF—stimulate angiogenesis during wound
healing.
Ischemic tissues, including those affected by myocardial infarction or peripheral
artery occlusion (e.g., limb ischemia), have also been a hotbed for study of the
effects of low O 2 on cellular recruitment and tissue regeneration. In particular, lack
of O 2 delivery to these diseased tissues results in HIF stabilization and subsequent
upregulation of recruitment chemokines, perhaps most importantly SDF-1, as well
as transmembrane proteins integrin β2 and ICAM-1 that facilitate adhesion of circulating cells to the damaged endothelium [33, 35, 51, 242]. Importantly, hypoxic
conditions also facilitate ECM remodeling through upregulation of proteases, such
as cathepsins and matrix metalloproteinases [4, 106, 226]. These factors, in concert
with HIF-induced production of other pro-angiogenic factors, such as VEGF, lead
to robust formation of neovasculature.
Oxygen-Sensing Mechanisms of Vascular Cells
Most cell types in the body respond to variations in O 2 tensions [233]. Gene expression, viability, metabolism, and the oxygen uptake rate of the cells change with
alterations in O 2 levels, in order to maintain homeostasis. When cells experience a
change in extracellular O 2 levels, they adapt to the new conditions, which may occur
rapidly. Hence, O 2 sensing in cells is expected to be controlled by well-organized,
highly sensitive mechanisms.
Several mechanisms have been proposed in the literature to account for O 2 sensing in cells. Although their sensitivities may differ from one another, more than one
such mechanism can coexist in a cell, resulting in various cellular responses. Within
the cell, the O 2 molecule mainly engages in two distinct processes: it is involved
directly in biosynthesis reactions; or it participates in metabolic processes, such as
the electron transport chain occurring in mitochondria. Any change in the concentration of O 2 extensively perturbs these processes and, following a sequence of
events, may have a number of different effects on the cell. Therefore, O 2 sensors in
cells can be mainly categorized as mitochondria-related sensors (bioenergetic) and
biosynthesis-related sensors (biosynthetic)—although they can be linked to each
other in some cases, making the distinction not completely clear [233].
Among the several effectors of O 2 -sensing mechanisms, HIFs are the most essential in terms of the diversity of their influences. The family of HIFα subunits (HIF1α,
HIF2α, and HIF3α) has been shown to be responsible for regulating expression of a
large number of genes, including those coding for key regulatory proteins of angiogenesis and vasculogenesis. Although HIFα is expressed at every oxygen tension, it
is rapidly ubiquitinated in normoxic conditions, resulting in its degradation. Thus,
the amount of intracellular HIFα protein depends on the balance between its expression and degradation. In conditions of low O 2 availability, all HIFα proteins heterodi4 Hypoxia and Matrix Manipulation for Vascular Engineering
strated that, during the burn wound-healing process, the accumulation of HIF1α
increases the number of circulating angiogenic cells, as well as smooth muscle actinpositive cells, in the wounded tissue. These hypoxic conditions—either directly or
indirectly through the accumulation of HIF—stimulate angiogenesis during wound
healing.
Ischemic tissues, including those affected by myocardial infarction or peripheral
artery occlusion (e.g., limb ischemia), have also been a hotbed for study of the
effects of low O 2 on cellular recruitment and tissue regeneration. In particular, lack
of O 2 delivery to these diseased tissues results in HIF stabilization and subsequent
upregulation of recruitment chemokines, perhaps most importantly SDF-1, as well
as transmembrane proteins integrin β2 and ICAM-1 that facilitate adhesion of circulating cells to the damaged endothelium [33, 35, 51, 242]. Importantly, hypoxic
conditions also facilitate ECM remodeling through upregulation of proteases, such
as cathepsins and matrix metalloproteinases [4, 106, 226]. These factors, in concert
with HIF-induced production of other pro-angiogenic factors, such as VEGF, lead
to robust formation of neovasculature.
Oxygen-Sensing Mechanisms of Vascular Cells
Most cell types in the body respond to variations in O 2 tensions [233]. Gene expression, viability, metabolism, and the oxygen uptake rate of the cells change with
alterations in O 2 levels, in order to maintain homeostasis. When cells experience a
change in extracellular O 2 levels, they adapt to the new conditions, which may occur
rapidly. Hence, O 2 sensing in cells is expected to be controlled by well-organized,
highly sensitive mechanisms.
Several mechanisms have been proposed in the literature to account for O 2 sensing in cells. Although their sensitivities may differ from one another, more than one
such mechanism can coexist in a cell, resulting in various cellular responses. Within
the cell, the O 2 molecule mainly engages in two distinct processes: it is involved
directly in biosynthesis reactions; or it participates in metabolic processes, such as
the electron transport chain occurring in mitochondria. Any change in the concentration of O 2 extensively perturbs these processes and, following a sequence of
events, may have a number of different effects on the cell. Therefore, O 2 sensors in
cells can be mainly categorized as mitochondria-related sensors (bioenergetic) and
biosynthesis-related sensors (biosynthetic)—although they can be linked to each
other in some cases, making the distinction not completely clear [233].
Among the several effectors of O 2 -sensing mechanisms, HIFs are the most essential in terms of the diversity of their influences. The family of HIFα subunits (HIF1α,
HIF2α, and HIF3α) has been shown to be responsible for regulating expression of a
large number of genes, including those coding for key regulatory proteins of angiogenesis and vasculogenesis. Although HIFα is expressed at every oxygen tension, it
is rapidly ubiquitinated in normoxic conditions, resulting in its degradation. Thus,
the amount of intracellular HIFα protein depends on the balance between its expression and degradation. In conditions of low O 2 availability, all HIFα proteins heterodi4 Hypoxia and Matrix Manipulation for Vascular Engineering