Department of Pathology,
Wellington School of Medicine,
Wellington South, New Zealand
To the Editor:
It was pleasing to see the electron microscopic study of early
experimental aneurysms by Kondo et al,1 a natural sequel
to previous experimental work on cerebral aneurysms by Profs Hashimoto
and Hazama. More space devoted to electron micrographs at higher
magnifications would have been preferable, and I concur with Dr
Rosenblum2 that apoptosis of vascular smooth muscle cells
(SMCs) is unproved.
Their mural thinning or atrophy progressing to aneurysmal dilatation is
similar to early aneurysmal changes in human cerebral
arteries3 and the experimental mural atrophy produced by
hemodynamic stress in experimental arterial bends,4
forks,5 and afferent arteries of arteriovenous
fistulas6 7 8 and classified as atrophic lesions of
atherosclerosis.9 Occurring at specified anatomic sites,
they are readily reproducible and in humans and experimentally may
eventually exhibit proliferative atherosclerotic
lesions.9 10 They develop initially as transversely
oriented tears of the internal elastic lamina (IEL)5 11 12
that precede endothelial disruption and secondary thrombus on the floor
of early IEL tears appearing in rabbits in 5 days and 2 days
postoperatively in common carotid and iliofemoral arteries,
respectively. Following rapid reendothelialization, tears continue
appearing in the IEL and deep medial elastic laminae without
endothelial disruption or thrombi, until eventually elastic tissue and
SMCs may disappear completely.4 8 Elastic disruption
should not be attributed, therefore, to a few platelets or leukocytes,
notable for their absence in the wall in these initial lesions. The
abrupt edges to the tears and microfractures in the
IEL13 14 15 are more consistent with bioengineering
fatigue16 than enzymatic digestion.17
Similarly elastic tears in developing human aortas are not associated
with platelets or leukocytes.18 Nor does the presence of
metalloproteinases in macrophages indicate a pathogenic role in
pathological fractures of elastic laminae or of the
intima9 10 any more than the presence of osteoclasts in
bone growth is responsible for pathological fatigue fractures of bones
and tendons. When intimal macrophages are most plentiful in
cholesterol-overloaded rabbits and in human familial
hypercholesterolemia, intimal tears and aneurysms are
characteristically absent.9 10
With such abrupt, extensive mural damage and elastic retraction and
possibly mural creep, eventual degeneration and disruption of
endothelium, SMCs, and the matrix seem to be induced by even greater
hemodynamic stresses than those responsible for the initial IEL
tears.10 In time, there is repair with superimposed
intimal proliferation. Transmission electron microscopy of early
lesions in rabbits exhibits findings15 16 17 similar to
those of Kondo et al.1 Misshapen SMCs and nuclei,
fragmentation of plasma membranes and matrix vesicle production, are
characteristic of human atherosclerosis9 10 and
reproducible in proliferative lesions of venous pouch
aneurysms19 and arteries and veins of experimental
arteriovenous fistulas.14 15
Necrotic debris in the matrix derives primarily from SMCs by
granulovesicular degeneration,9 10 whereas that from
endothelium is readily washed downstream. Similar vesiculation
occurring in erythrocytes is accentuated by hypertension, vigorous
sport, and marathons, with the production of hemolytic anemia.
Turbulence associated with cardiac valve stenosis and arteriovenous
fistulas is accompanied by a shortened erythrocytic life span, thus
supporting the concept that the vesiculogranular degeneration of SMCs
(and probably of endothelium) is also mechanically induced, resulting
from bioengineering fatigue and usage rather than genetically
programmed cell death.9 10
Matrix vesicles are unlikely to be lysosomal, although lysosomes and
nuclear debris may appear in the matrix with progressive degeneration
of SMCs, which at times disintegrate into a myriad of vesicles of
variable size lying in the midst of dystrophic basement
membranes.9 10 Matrix vesicles in early atrophic lesions
are not as plentiful as in proliferative lesions, which include early
intimal thickenings in human cerebral arterial forks20 and
rabbit renal arterial forks.21 These matrix vesicles occur
in arteries of all sizes, including arterioles, and are augmented in
experimental hypertension, experimental arteriovenous fistulas
(arteries and veins), and experimental venous pouch aneurysms and
atherosclerosis.9 10 They are associated with the early
appearance of lipid in cerebral arteries and sheep arteriovenous
fistulas as nonphagocytosed cell debris and necrotic cells that have an
affinity for lipid and calcification.9 These
ultrastructural, degenerative cellular changes are hemodynamically
induced and are not apoptotic or programmed cell death, as is so often
alleged. "Apoptosis" is frequently used indiscriminately and at
times assumed, the necrosis occurring secondarily to as-yet
undetermined or ill-understood causes.
There is no scientific evidence to support a dominant role of shear
stress in atherogenesis and aneurysm formation. When analyzed, shear
stress at the wall/blood interface proves to be an insufficient
explanation. Atrophic lesions must be due to transmural stress and have
been attributed to the pulsatile pressure head of the main flux of
blood impacting on the wall at arterial forks and the greater curvature
of bends superimposed on the repetitive distensile and elongating
effect of the rapidly traveling pulse pressure of 40 to 100
mm Hg.10 Afferent arteries of arteriovenous fistulas are
subjected to greatly increased flow and pulse pressures immeasurable
larger than the relatively insignificant shear stresses (12 to 15
dynes/cm2) transmitted through the thin endothelium and its
attachments to the underlying matrix.10 22 For the wall to
dilate, yield of all mural connective tissues, including the
adventitia, is necessary, and this presupposes transmural stress.
Hypothetical explanations currently in vogue regarding underlying
mechanisms do not detract from the important contribution of Profs
Hashimoto and Hazama in the experimental production of cerebral
aneurysms, their observations1 lending further evidence to
the assertion that such lesions are indeed biomechanically
(hemodynamically) induced.
References
Department of Neurosurgery,
Neurological Institute,
Nagahama City Hospital,
Shiga, Japan
Department of Neurosurgery,
Kyoto University Medical School and Hospital,
Kyoto, Japan
We would like to express our gratitude to Prof Stehbens for his
interest in our recent article in Stroke1 and
thank the editor for the opportunity to reply to his letter. We also
regret that more space was not available for electron micrographs.
In our article, we demonstrated the apoptosis of the medial smooth
muscle cells not only by electron microscopy but also by specific
immunolabeling of nuclear DNA fragmentation with terminal
deoxynucleotidyl transferase, although the frequency was not so high.
The disappearance of cells through apoptosis, or rather of the
apoptotic bodies that such cell death leaves behind, is extremely
rapid.2 Therefore, it is difficult to definitively prove as
well as deny the apoptosis in vivo with only ultrastructural findings.
A small proportion of apoptotic cells visualized in a tissue section
can represent a cell loss of considerable magnitude.3
Although there may have been relatively few apoptotic cells at any
point in time, this does not deny the participation of apoptosis as a
mode of cell death, as Prof Rosenblum mentioned in the editorial
comment on our article.4 Although our study implied the
importance of apoptosis in the production of the aneurysms, the
evidence was not definite, and we do not assume that only apoptosis
(that is, programmed cell death) is responsible for the disappearance
of smooth muscle cells in the development of cerebral aneurysms in
rats.5
Prof Stehbens stated that mechanical hemodynamic stress directly causes
bioengineering fatigue of internal elastic laminae6 and
"vesticulogranular degeneration" of medial smooth muscle cells and
endothelial cells.7 8 We agree that this direct mechanical
force can play an important role in the development of cerebral
aneurysms. Release of smooth muscle cells by direct hemodynamic stress
from the extracellular matrix, a cell survival factor,9 may
be a trigger of apoptosis. Furthermore, increased hemodynamic stress
may induce synthesis of endonucleases via expression of the required
genes and their message.
In vessels, as in other organs, complex systems may be involved in the
control of their structure in response to surrounding conditions. The
role of the endothelial cell as a mechanosensor perceiving wall shear
stress10 and the relationship between medial smooth muscle
cells with various cytokines or other endothelium-derived factors such
as nitric oxide11 can not be disregarded. The
endothelium-denuded artery did not disclose the dilated response to
increased blood flow.12 Furthermore, matrix
metalloproteinase-9 in macrophage-like cells has been reported to be
important for the degradation of elastic fibers in the aortic
explants,13 although few macrophage-like cells were found
in the wall in early aneurysmal changes in rats. Matrix
metalloproteinase-2 has also been found localized within the cytoplasm
of the SMCs.14
Professors Stehbens and Rosenblum kindly advocated the need for further
investigations on biochemical aspects, including expression of genes
regulating apoptosis, in our experimentally induced
aneurysms,5 which are now underway in our laboratory.
References
© 1998 American Heart Association, Inc.
Letters to the Editor
Apoptosis and Matrix Vesicles in the Genesis of Arterial Aneurysms of Cerebral Arteries
Response
Key Words: muscle, smooth • apoptosis • cerebral aneurysm
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