85
the capacity to contribute to revascularization of ischemic tissues [224]. Similarly,
HIF1α also induces the differentiation of peripheral blood mononuclear cells into
EPCs, and hypoxia stimulates the further differentiation of EPCs into mature ECs
[8, 117].
All of these findings highlight the significance of O 2 tension as a critical parameter to control vascular differentiation of pluripotent or multipotent cells. Although
some of these studies suggest contrary hypotheses, the importance of O 2 considerations in cell culture environments cannot be overstated, as O 2 tension can be
manipulated to prevent spontaneous differentiation of pluripotent cells and to
enhance the efficiency of the differentiation into EPCs and mature ECs.
4.2.2 Vascular Responses to ECM
In the human body, vascular cells are surrounded by diverse components of the
ECM, the unique spatial and temporal distribution of which affects GF availability
and matrix properties which, in turn, regulate vasculogenesis and angiogenesis. Just
like oxygen tension, which varies throughout vascular development, ECM components are also uniquely distributed; for example, hyaluronic acid (HA; also known
as hyaluronan) levels were found to be highest during embryogenesis and to be
replaced by fibronectin and then collagen, which remains abundant throughout
adulthood. In this section we will discuss ECM distribution and its effects on vascular development and maintenance. Then, we will discuss various ECM components
that affect vascular morphogenesis. Lastly, we will describe strategies for manipulating the ECM using synthetic biomaterials and emerging technology.
4.2.2.1 Types of ECM Found Participating in Vascularization
The ECM surrounding blood vessels contributes significantly to their diverse functions and complexity. This ECM diversity encompasses different vascular development periods (i.e., embryonic versus adult) and specialized vessels at various
locations in the body (i.e., capillary, arteriole, and venule) or tissues in the body
(i.e., heart, kidney, lung, etc.). During early vascular development, the ECM provides informational cues to the vascular cells, thus regulating their differentiation,
proliferation, and migration. Fibronectin and HA, which are major components of
the embryonic ECM, have been shown to be vital regulators for vascularization during embryogenesis [222]. Fibronectin, a unique glycoprotein, contains cell adhesion
and heparin-binding sites that synergistically modulate the activity of VEGF to
enhance angiogenesis [236]. Various lineage studies have found developmental
abnormalities in embryonic hearts and vessels in fibronectin-null mice, suggesting
its crucial role in mediating EC interactions [14, 71]. The levels of hyaluronan, a
nonsulfated linear polysaccharide, are greatest during embryogenesis and then
decrease at the onset of differentiation [221], where it plays a crucial role in
4 Hypoxia and Matrix Manipulation for Vascular Engineering
the capacity to contribute to revascularization of ischemic tissues [224]. Similarly,
HIF1α also induces the differentiation of peripheral blood mononuclear cells into
EPCs, and hypoxia stimulates the further differentiation of EPCs into mature ECs
[8, 117].
All of these findings highlight the significance of O 2 tension as a critical parameter to control vascular differentiation of pluripotent or multipotent cells. Although
some of these studies suggest contrary hypotheses, the importance of O 2 considerations in cell culture environments cannot be overstated, as O 2 tension can be
manipulated to prevent spontaneous differentiation of pluripotent cells and to
enhance the efficiency of the differentiation into EPCs and mature ECs.
4.2.2 Vascular Responses to ECM
In the human body, vascular cells are surrounded by diverse components of the
ECM, the unique spatial and temporal distribution of which affects GF availability
and matrix properties which, in turn, regulate vasculogenesis and angiogenesis. Just
like oxygen tension, which varies throughout vascular development, ECM components are also uniquely distributed; for example, hyaluronic acid (HA; also known
as hyaluronan) levels were found to be highest during embryogenesis and to be
replaced by fibronectin and then collagen, which remains abundant throughout
adulthood. In this section we will discuss ECM distribution and its effects on vascular development and maintenance. Then, we will discuss various ECM components
that affect vascular morphogenesis. Lastly, we will describe strategies for manipulating the ECM using synthetic biomaterials and emerging technology.
4.2.2.1 Types of ECM Found Participating in Vascularization
The ECM surrounding blood vessels contributes significantly to their diverse functions and complexity. This ECM diversity encompasses different vascular development periods (i.e., embryonic versus adult) and specialized vessels at various
locations in the body (i.e., capillary, arteriole, and venule) or tissues in the body
(i.e., heart, kidney, lung, etc.). During early vascular development, the ECM provides informational cues to the vascular cells, thus regulating their differentiation,
proliferation, and migration. Fibronectin and HA, which are major components of
the embryonic ECM, have been shown to be vital regulators for vascularization during embryogenesis [222]. Fibronectin, a unique glycoprotein, contains cell adhesion
and heparin-binding sites that synergistically modulate the activity of VEGF to
enhance angiogenesis [236]. Various lineage studies have found developmental
abnormalities in embryonic hearts and vessels in fibronectin-null mice, suggesting
its crucial role in mediating EC interactions [14, 71]. The levels of hyaluronan, a
nonsulfated linear polysaccharide, are greatest during embryogenesis and then
decrease at the onset of differentiation [221], where it plays a crucial role in
4 Hypoxia and Matrix Manipulation for Vascular Engineering