82
amount of pyruvate that flows into the TCA cycle and therefore decreases aerobic
respiration in mitochondria [171]. In addition, the increases in both the transcription
and expression of glucose transporter protein 1 (GLUT-1) were shown to be HIF1αdependent in hypoxic conditions [7]. In other words, deactivation of PHDs and FIHs
at low O 2 levels leads to the stabilization of HIFα, which then reduces O 2 aerobic
respiration by inducing pyruvate degradation while, at the same time, promoting
glycolysis by increasing the expression of glucose transporter proteins. Another
proposed mechanism involves the inhibition of cytochrome oxidase by NO, which
is known to be regulated by shear stress and O 2 tension. NO influences mitochondrial respiration by the competitive inhibition of cytochrome oxidase with O 2 and by
inhibiting electron transfer between cytochrome b and c, therefore increasing ROS
production [26].
The effects of blood flow and O 2 tension are crucially important for the ECs
comprising the vessel walls, since these conditions can be perturbed in many pathophysiological situations in the body. Some studies have shown mitochondrial respiration of ECs to be lower than other cell types, suggesting that most of the O 2
consumption is non-mitochondrial [78, 223]. Helmlinger et al. demonstrated that
ECs consume O 2 during capillary formation, whereas they also preserve and expand
the capillary structures, even under severe hypoxia (about 0.6% O 2 ), by upregulating VEGF expression [93]. It is not surprising that ECs possess a special type of
metabolism—aerobic glycolysis in their resting state (physiological conditions) and
anaerobic glycolysis in their navigating state (hypoxic conditions)—since O 2 is
transported through ECs to other tissues, and thus they must possess the ability to
survive and commence angiogenesis under hypoxic conditions [70].
Moreover, when ECs are exposed to excess glucose, their ATP generation shifts
to glycolysis, and lactate levels, increased as a by-product of glycolysis, contribute
to the inactivation of PHDs and, therefore, the stabilization of HIFα [240]. Where
blood flow is perturbed, such as in ischemia and wound healing, both NO and O 2
levels are changed in blood vessels, and all of the metabolic variations discussed
become more important.
Transcription of Angiogenic Genes
Manalo et al. showed in their study of ECs that 245 genes are upregulated and 325
genes are downregulated at least 1.5-fold in response to hypoxia and HIF1α. These
genes are responsible for the expression of collagens, GFs, receptors, and transcription factors, all of which are significant for the processes of angiogenesis and vasculogenesis. This wide range of hypoxia-related transcription factors also indirectly
affects HIF1α. The genes directly regulated by HIF1α include VEGF-A, VEGFR-1,
Flt1-1, and erythropoietin (EPO). Examples of indirectly regulated genes include
fibroblast growth factor (FGF), placental growth factor (PLGF), platelet-derived
growth factor (PDGF), angiopoietins (ANG-1 and ANG-2), and Tie-2, the receptor
of ANGs [68]. Although VEGF is the major GF that stimulates blood vessel formation, when it alone was transgenically overexpressed in mice, defective blood
M. R. Blatchley et al.
amount of pyruvate that flows into the TCA cycle and therefore decreases aerobic
respiration in mitochondria [171]. In addition, the increases in both the transcription
and expression of glucose transporter protein 1 (GLUT-1) were shown to be HIF1αdependent in hypoxic conditions [7]. In other words, deactivation of PHDs and FIHs
at low O 2 levels leads to the stabilization of HIFα, which then reduces O 2 aerobic
respiration by inducing pyruvate degradation while, at the same time, promoting
glycolysis by increasing the expression of glucose transporter proteins. Another
proposed mechanism involves the inhibition of cytochrome oxidase by NO, which
is known to be regulated by shear stress and O 2 tension. NO influences mitochondrial respiration by the competitive inhibition of cytochrome oxidase with O 2 and by
inhibiting electron transfer between cytochrome b and c, therefore increasing ROS
production [26].
The effects of blood flow and O 2 tension are crucially important for the ECs
comprising the vessel walls, since these conditions can be perturbed in many pathophysiological situations in the body. Some studies have shown mitochondrial respiration of ECs to be lower than other cell types, suggesting that most of the O 2
consumption is non-mitochondrial [78, 223]. Helmlinger et al. demonstrated that
ECs consume O 2 during capillary formation, whereas they also preserve and expand
the capillary structures, even under severe hypoxia (about 0.6% O 2 ), by upregulating VEGF expression [93]. It is not surprising that ECs possess a special type of
metabolism—aerobic glycolysis in their resting state (physiological conditions) and
anaerobic glycolysis in their navigating state (hypoxic conditions)—since O 2 is
transported through ECs to other tissues, and thus they must possess the ability to
survive and commence angiogenesis under hypoxic conditions [70].
Moreover, when ECs are exposed to excess glucose, their ATP generation shifts
to glycolysis, and lactate levels, increased as a by-product of glycolysis, contribute
to the inactivation of PHDs and, therefore, the stabilization of HIFα [240]. Where
blood flow is perturbed, such as in ischemia and wound healing, both NO and O 2
levels are changed in blood vessels, and all of the metabolic variations discussed
become more important.
Transcription of Angiogenic Genes
Manalo et al. showed in their study of ECs that 245 genes are upregulated and 325
genes are downregulated at least 1.5-fold in response to hypoxia and HIF1α. These
genes are responsible for the expression of collagens, GFs, receptors, and transcription factors, all of which are significant for the processes of angiogenesis and vasculogenesis. This wide range of hypoxia-related transcription factors also indirectly
affects HIF1α. The genes directly regulated by HIF1α include VEGF-A, VEGFR-1,
Flt1-1, and erythropoietin (EPO). Examples of indirectly regulated genes include
fibroblast growth factor (FGF), placental growth factor (PLGF), platelet-derived
growth factor (PDGF), angiopoietins (ANG-1 and ANG-2), and Tie-2, the receptor
of ANGs [68]. Although VEGF is the major GF that stimulates blood vessel formation, when it alone was transgenically overexpressed in mice, defective blood
M. R. Blatchley et al.