Role of Hypoxia in the Evolution and Development of the Cardiovascular System Page: 1,340
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FISHER AND BURGGREN
which 02 serves as a cofactor. The 02-dependent posttransla-
tional modification of HIF-a protein leads to binding of the von
Hippel-Lindau (VHL) factor followed by proteasomal degra-
dation. As 02x concentrations decrease, PHD activity is re-
duced, leading to accumulation of HIF-a, which, through its
dimerization partner HIF-/3 (ARNT), binds DNA and regulates
the transcription of multiple hypoxia-responsive genes.
The constituents of this pathway were originally identified
in mammalian cells [reviewed in (62, 87, 95) and elsewhere in
this series]. Orthologues of HIF, PHD, and VHL have subse-
quently been identified throughout the animal kingdom, in-
cluding the nematode worm Caenorhabditis elegans (30, 48).
Adult C. elegans are only 1 mm in length and several cell lay-
ers thick. They have become a favored model organism because
of their simplicity at maturity (< 1,000 cells) combined with ev-
idence for conservation of life processes that are relevant to
more-complex animals. Oxygen delivery is accomplished by
diffusion from the surrounding medium. The presence in the
worm of a hypoxia/HIF-inducible transcriptional program (30,
48) suggests that it originally evolved as a cell autonomous sys-
tem for defense against 02 deprivation. Unlike larger and more
complex animals, C. elegans can survive at ambient 02 con-
centrations as low as 0.1%. Under 02 deprivation, C. elegans
reduces energy expenditure by limiting motility, feeding, and
metabolism (70, 71) .This strategy of energy conservation in
the setting of reduced 02 availability is used by worms and even
some lower vertebrates that are termed "hypoxia tolerant." This
may be viewed as analogous to hibernation in more-complex
animals, as well as the downregulation of energy expenditure
in the face of reduced energy supplies that occurs in the myo-
cardial cells and other cell types of more-advanced organisms
(9, 19, 24, 111). In C. elegans and cells of other organisms, the
alternative strategy of increasing energy supply through a
switch to anaerobic metabolism (glycolysis) in response to 02
deprivation is also used (Pasteur effect). This is dependent on
the hypoxia/HIF-dependent upregulation of glucose trans-
porters and glycolytic enzymes. Because of the accumulation
of lactic acid as the byproduct of glycolysis, the switch to anaer-
obic metabolism by itself is self-limiting. Deletion of the HIF
gene from C. elegans limits survival in severe hypoxia (0.1%
02) (48, 90), suggesting that the evolutionarily early function
of HIF was to promote cell survival under conditions of oxy-
gen deprivation, at least in part through induction of stress-re-
sponse genes and changes in cellular metabolism.
In C. elegans, as in almost all cells tested, hypoxia results in
the induction of the prolyl hydroxylases, serving as a negative-
feedback regulator of the hypoxic signal. In C. elegans, as in
other animals, some genomic responses to hypoxia are still ev-
ident after HIF ablation (90), suggesting HIF-independent
mechanisms for gene-based responses to hypoxic stress.
Whether these represent more-generalized stress responses, or
are specifically induced in response to 02 deprivation in a man-
ner analogous to HIF, is not yet clear.
Evolution of respiratory systems for
As larger, multicellular animals evolved, simple diffusion be-
came inadequate as a method of 02 delivery to tissues (Fig. 1).
The size at which a convective system for oxygen delivery is
FIG. 1. The relation between body size, metabolic rate, and
the ability of simple diffusion to provide adequate oxy-
genation of small animals. Generally, animals falling in the
"diffusion zone" on this figure can supply all of their oxygen
needs by diffusion, but as body size or metabolic rate or both
increase, the need for an internal convection of body fluids in-
creases. Exceptions are large animals with unusually low meta-
bolic rates, or small animal with unusually large metabolic rates.
(From Burggren and Reiber, 2007).
required can be estimated based on the rate of diffusion of 02,
the 02 gradient driving diffusion, and 02 consumption. At sea
level, the partial pressure of 02 in the atmosphere is -150 mm
Hg, and assuming an anoxic core and Krogh's constant of oxy-
gen diffusion of 0.045 /,mol/cm/sec/mm Hg, the maximum size
for effective 02 uptake by diffusion is -2 mm (15). Clearly, if
animals were to evolve into larger and more-complex organ-
isms, new systems for oxygen and substrate delivery and meta-
bolic waste removal would have to be developed. This is known
as the environmental gatekeeper theory for molecular oxygen,
which suggests that the Cambrian era explosion in biologic di-
versity came about as animals evolved systems for more-ef-
fective delivery and utilization of oxygen [reviewed in (55)].
The fruit fly Drosophila has an intermediate level of com-
plexity, with developed cardiac and respiratory systems. The
presence of these more-simplified organ systems, combined
with their ease of rearing and genetic manipulation via inser-
tional mutagenesis, has made the fruit fly a favored model or-
ganism for experimental study. The orthologues for the HIF-
dependent hypoxia signaling system have been described in a
number of invertebrates, including Drosophila and other in-
sects, and is thus thought to be common to arthropods and bi-
laterians [reviewed in (41)]. The cardiovascular systems of in-
sects and other arthropods do not contain 02-binding pigments
(hemoglobin in higher eucaryotes), and thus the circulating he-
molymph is thought not to play a role in oxygen transport. In-
stead, 02 delivery to the cells in these animals occurs primarily
via its distribution in gas through the tracheal system [reviewed
in (41)]. Tracheal cells are specified at midgestation Drosophila
under the control of the bHLH/PAS family member TRA-
CHEALESS, a binding partner for the HIF-la/ARNT ortho-
logue TANGO [reviewed in (41)]. These cells then migrate to
regions where the tracheal system forms under the control of
the fibroblast growth factor (FGF) ligand and receptor ortho-
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Fisher, Steven A. & Burggren, Warren W. Role of Hypoxia in the Evolution and Development of the Cardiovascular System, article, 2007; [New Rochelle, New York]. (digital.library.unt.edu/ark:/67531/metadc115191/m1/2/: accessed July 25, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.