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Leukemia (2006) 20, 1209–1210
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COMMENTARY
Aristotle: the first student of angiogenesis
E Crivellato1 and D Ribatti2
1
Department of Medical and Morphological Researches, Anatomy Section, University of Udine Medical School, Udine, Italy and
Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
2
Leukemia (2006) 20, 1209–1210. doi:10.1038/sj.leu.2404256;
published online 4 May 2006
The cardiovascular system is the first functional organ system to
develop in the vertebrate embryo. Several genetic and
epigenetic (vascular branching, pruning and remodeling)
mechanisms are involved in the early development of the
vascular network.1
A widely accepted view is that blood vessels arise through
two mechanisms during development: vasculogenesis and
sprouting angiogenesis.2 A third mechanism has also been
described, the so-called non-sprouting angiogenesis or intussusceptive microvascular growth, which occurs by splitting of the
existing vasculature by transluminal pillars or transendothelial
bridges.3 Intussusceptive microvascular growth has been described during angiogenesis in solid and hematological
tumors.4,5
The term angiogenesis applies to the formation of capillaries
from pre-existing vessels, that is, capillaries and post-capillary
venules. The vascularization of many extra-embryonic and
intra-embryonic tissues, including the yolk sac, embryonic
kidney, thymus, brain, limb and choroid plexus, occurs by
sprouting angiogenesis.2
During embryonic life, however, blood vessels first occur as a
result of the process of vasculogenesis, which consists in the
development of vascular channels from endothelial cells
differentiating in situ from groups of mesoderm-derived angioblasts.6 The vascular network of certain endodermal organs,
including the liver, lungs, pancreas, stomach/intestine and
spleen, occurs indeed by vasculogenesis.
Several observations indicate that vasculogenesis may not be
restricted to early embryogenesis, but may also have a
physiological role or contribute to the pathology of vascular
diseases in adults.7 The major evidence in favor of this new view
comes from demonstration of the presence of circulating
endothelial cells and endothelial precursor cells and newly
described mechanisms of blood vessel formation in tumor
growth.
This is the way the primitive heart and the primitive vascular
plexus are formed. Remodeling and expansion of these primary
vessels through both pruning and vessel enlargement results in a
closely interconnecting branching pattern. The vascular system
is a highly heterogenous and non-uniform organ system, in
which the organotypic differentiation of endothelial cells is
Correspondence: Professor D Ribatti, Department of Human Anatomy
and Histology, University of Bari Medical School, Piazza Giulio
Cesare 11, Policlinico, I-70124 Bari, Italy.
E-mail: [email protected]
Received 28 March 2006; accepted 5 April 2006; published online 4
May 2006
dependent on interactions with stromal parenchymal cells in the
target tissues.8
Remarkably, the dawn of this model, which is currently held
as the orthodox view in developmental biology, routes back to
the greatest of classical biologists, Aristotle.
Aristotle was born in Stagira, a Greek colony in the northern
Aegean coast, in 384 BC. His father was court physician to king
Amyntas of Macedonia and his mother also came from a family
of physicians. At the age of 17, Aristotle moved to Athens, the
intellectual center of the world, where he attended Plato’s
Academy for 20 years, until the death of his master. Aristotle
soon developed a great passion for the investigation of the
natural facts and the study of the physical laws. In 343 BC, he
became tutor of Alexander the Great and around 335 BC, after
Alexander departure for his Asiatic campaign, he founded with
Theophrastus, a young man with large interests in plant biology,
a ‘school’ in Athens known as the Lyceum or the Peripatetic
School. He headed this school for 13 years and during this
period he composed the greater number of his writings. At last
he died in 322 BC, after retiring to his mother’s birthplace, the
island of Euboea.
Aristotle was not only one of the most influential theoretical
philosophers and logicians, but he was properly recognized as
the founder of both the science of biology and the philosophy of
biology as distinct branches of episteme (the human knowledge).9 He was indeed the first scholar who undertook an
extensive and systematic investigation of the living world as a
separate field of inquiry, with its own special concepts and
principles.9 His experimental discoveries and general doctrines
on animals and the living matter represented seminal events in
the history of biology. More than two thousand years after
Aristotle’s original work, many of his observations still appear so
accurate, skillful and sophisticated to induce our unconditioned
admiration. Yet, the extension of his biological interests and the
importance of his investigative achievements remained unrivalled until the 16th century and deeply influenced the
development of forthcoming speculation on natural philosophy.
This does not mean that his biological treatises would not
contain observational and conceptual mistakes, but the magnitude and the quality of his work were absolutely outstanding.
More than 500 different species of animals, including about 120
kinds of fish and 60 kinds of insects, were referred to in his
biological works.10 He was the first to practice dissections
extensively and systematically, although not in adult humans.
He claimed, however, having examined a 40-day-old human
fetus. He collected in a series of biological treatises both the
enormous mass of recorded observations and the theoretical
principles that guided his investigative work. In addition to the
three works traditionally referred to as History of Animals
(Historia animalium), Parts of Animals (De partibus animalium)
and Generation of Animals (De generatione animalium), there
are a number of briefer ‘essays’ on more specialized topics: on
animal motion, on animal locomotion, on respiration, on life
Aristotle and angiogenesis
E Crivellato and D Ribatti
1210
and death, on youth and old age, on length and shortness of life,
on sleeping and waking, on the senses and their objects (the last
six being included in the so-called Parva naturalia). According
to Aristotle, the objective of any inquiry, in particular of
inquiries regarding natural phenomena, was to elaborate a
system of hierarchically organized concepts and propositions,
ultimately resting on knowledge of the essential natures of the
objects of study, the essence or form. This notion had a
prominent position in Aristotle’s biological reasoning. Form was
what made that individual animal what it actually was. In
contrast to some earlier philosophers, like Empedocles and the
atomists, Aristotle was confident on a rational plan and a logical
design governing all biological events.10 Everything in nature
has its end and function, he was accustomed to repeat. Indeed,
as we will see also in this short article, the concepts of hierarchy
and teleology played a crucial role in his attitude of explaining
biological phenomena.
Aristotle was clear in his mind on the notion that the heart,
along with blood vessels, was the first structure to appear during
embryogenesis. In many passages of his biological books, he
claimed that the heart was the primary organ to become visible
in vertebrates (‘blooded animals’ as they were called by
Aristotle) and to reveal the essential attitude of living things
that is motion. In De partibus animalium (PA III 4 666a 22), he
likened the heart to a living creature11 and in Historia
animalium (HA VI 3 561a 4), while describing the early stages
of chick development in the egg, he wrote that ‘the first signs of
the embryo are seen after three days and three nightsy and the
heart is no bigger than just a small blood spot in the white. This
spot beats and moves as though it were alive’.12 Aristotle
interpreted this finding as an essential point corroborating his
general opinion that the heart was the principle of life and the
seat of perceptive and nourishing soul (De juventute et senectute
3 469a 6; De generatione animalium GA II 5 741b 15).11,13
Being thus the source of the embryo’s sustenance and the
organizer of the developmental process (GA II 6 742b 34), it was
not surprising that just the heart would be the first organ to
appear. Remarkably, he recognized that the heart was in early
connection to blood vessels (PA III 666a 1; HA VI 3 561a 13),
thus identifying a close embryological and functional link
between them. The explanation Aristotle provided for the
simultaneous occurrence of heart and vasculature was essentially teleological, insofar as he asserted that blood was the
body’s nourishment and therefore it had to flow from the heart to
the whole organism as early as possible (PA III 4 666a 7). In his
idea of embryologic development as a step by step process,
Aristotle allocated great significance to the growth and
expansion of the organism according to an original vascular
design. Remarkably, he regarded the organization of blood
vessels as the basic schema for embryo patterning. He
maintained indeed that blood vessels were the first structures
to undergo remodeling during the early embryologic life (GA IV
Leukemia
1 764b 28) and this would explain why the different segments of
the body were all situated around the vascular channels like
around a model framework (GA IV 764b 30). Vessels extended
from the heart and permeated all body’s parts because they must
guarantee nourishment to them (GA II 743a 1). Elsewhere,
Aristotle recognized that the heart was the first organ to be
replenished with blood (PA III 4 666a 10). Accordingly, he
explicated this observation by admitting that the heart would be
the first repository and the source of blood (PA III 4 666a 8). This
notion now appears of outstanding significance because it
implicitly shapes the concept that the heart and the blood have a
common derivation. Translated into today’s language, this
means that both descend from a common endothelial and
hematopoietic progenitor, the putative hemangioblast, in the
embryonic mesoderm.14
The aim of this brief historical note was to convey the sense
of the investigative skill as well as of the speculative depth
and complexity of Aristotle’s biological approach. In this
context, remarkable is his contribution to the early definition
of some basic concepts in vascular development, which
represent a crucial target even for contemporary biologists and
embryologists.
References
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