ANTIOXIDANTS & REDOX SIGNALING
Volume 9, Number 9, 2007
Mary Ann Liebert, Inc.
Role of Hypoxia in the Evolution and Development of the
STEVEN A. FISHER1 and WARREN W. BURGGREN2
How multicellular organisms obtain and use oxygen and other substrates has evolved over hundreds of mil-
lions of years in parallel with the evolution of oxygen-delivery systems. A steady supply of oxygen is critical
to the existence of organisms that depend on oxygen as a primary source of fuel (i.e., those that live by aero-
bic metabolism). Not surprisingly, a number of mechanisms have evolved to defend against oxygen depriva-
tion. This review highlights evolutionary and developmental aspects of 02 delivery to allow understanding of
adaptive responses to 02 deprivation (hypoxia). First, we consider how the drive for more efficient oxygen
delivery from the heart to the periphery may have shaped the evolution of the cardiovascular system, with
particular attention to the routing of oxygenated and deoxygenated blood in the cardiac outlet. Then we con-
sider the role of 02 in the morphogenesis of the cardiovascular system of animals of increasing size and com-
plexity. We conclude by suggesting areas for future research regarding the role of oxygen deprivation and
oxidative stress in the normal development of the heart and vasculature or in the pathogenesis of congenital
heart defects. Antioxid. Redox Signal. 9, 1339-1352.
EVOLUTION OF OXYGEN
STRESS RESPONSES, AND
The early oxygen environment
O XYGEN BEGAN TO ACCUMULATE on earth several billion
years ago in photosynthetic reactions in which energy
from the sun was used to convert carbon dioxide and water into
sugar, with oxygen as a waste product. The accumulation of
large amounts of oxygen was likely initially toxic, leading to
what is termed the Oxygen Catastrophe, also called the Oxy-
gen Crisis or Great Oxidation (40). This increase in environ-
mental oxygen -2.4 billion years ago is postulated to have
caused a massive die-off in obligate anaerobic organisms (bac-
teria) and may have provided the opportunity for expansion of
organisms that could both defend against oxidative stress and
use oxygen. Over time, 02x came to be highly abundant in the
earth's air (-21% 02/79% N2) and water (solubility of -5
ml/L), with the 02 content dependent on environmental factors
such as atmospheric pressure, temperature, and water salinity.
Evolution of biochemical/metabolic responses to
That a continuous 02 supply was critical to the survival of
the simple multicellular eukaryotic aerobic organisms that first
evolved is suggested by the presence of a phyletically ancient
gene-based system to defend against changes in 02 availabil-
ity. The primary biochemical pathway for gene-based defenses
against 02 deprivation is the induction of the hypoxia-inducible
transcription factor (HIF) [reviewed in (87)] and elsewhere
in this series]. The accumulation of the HIF-a subunit
(-1, 2, 3) is suppressed under normoxic conditions by its hy-
droxylation by the prolyl 4-hydroxylases (PHD), a reaction in
1Case Western Reserve School of Medicine, Cleveland, Ohio.
2University of North Texas, Denton, Texas.
Fisher, Steven A. & Burggren, Warren W. Role of Hypoxia in the Evolution and Development of the Cardiovascular System. [New Rochelle, New York]. UNT Digital Library. http://digital.library.unt.edu/ark:/67531/metadc115191/. Accessed March 6, 2015.