W. A. THOMAS, R. A. FLORENTIN, S. C. NAM, J. M. REINER AND K. T. LEE 
863 
pretable information on atherogenesis than 
studies of lesions. Was increased arterial meta- 
bolic activity a feature long before the develop- 
ment of gross lesions, or was it preceded by a 
phase in v^^hich one or more metabolic functions 
were depressed ? 
We decided to study metabolic features in the 
period beginning with the first day on diet on a 
continuing basis until the development of gross 
lesions, approximately one month later. In the 
first study in this series^ we found that swine 
fed the mild diet had increased DNA synthesis 
in their arteries in the first 10 days on diet. In a 
subsequent study we demonstrated a higher 
rate of entry of arterial SMC into mitoses as 
early as 8 days on diet,* reflecting increased 
numbers synthesizing DNA. Oxygen uptake in 
this early period was also elevated.^ Other met- 
abolic features have not as yet been intensively 
studied; but it seems likely that at least some 
others will show a similar pattern. The mitosis 
study is illustrated in Table III. 
Thus increased activity, at least in DNA syn- 
thesis, and oxygen consumption, begins shortly 
after the diet is started, long before develop- 
ment of gross atherosclerotic lesions and even 
before a m.easurable increase in cholesterol con- 
centration in the arterial wall has been demon- 
strated. No depression of any metabolic func- 
tion has as yet been demonstrated in this early 
period on diet. However, by electron micro- 
scopy, counts have been made of arterial SMC 
that appear to be dead or dying in swine fed the 
mild diet for 8 days ; and the numbers are some- 
what greater than in controls.^^ 
The increase in number of SMC synthesizing 
DNA so early after beginning the cholesterol 
diet is reminiscent of the increase in DNA syn- 
thesis in salivary glands shortly after a paren- 
teral injection of isoproterenol. It is also rem- 
iniscent of the increase in DNA synthesis that 
occurs throughout the remaining liver after 
Table III. — Mitotic counts of aortic trifurcation re- 
gion of swine fed cholesterol for three days, expressed 
as numbers of mitoses per 10'^ cells per hour 
Cholesterol 
Control 
p value* 
Endothelium 
2.3 
1.1 
<.01 
Subondothelial intima 
3.2 
1.5 
<.01 
Inner media 
4.0 
1.9 
<.01 
* Mann- Whitney U-test. 
partial hepatectomy.^^ In both of these latter 
situations it has been postulated that the drug 
or procedure has resulted in an effect being pro- 
duced on the control mechanism of DNA syn- 
thesis in specific cell types of the affected organ. 
Intensive studies are underway in many labora- 
tories in an attempt to clarify the cellular 
events accounting for the change. Similar stud- 
ies seem indicated in order to clarify events in 
arterial SMC altered by cholesterol feeding. 
One of the first things that needs to be known 
is what part or parts of the arterial SMC re- 
productive cycle has been changed. Figure 1 
shows the basic features of the cell reproductive 
cycle as it is currently understood. In most tis- 
sues only a part of the total cell population is in 
the reproductive cycle at any one time. The 
other cells in the tissue, which would generally 
be those performing the specialized function of 
the tissue (e.g., contraction in SMC), have left 
the reproductive cycle. Some of these are prob- 
GENERATION 
CYCLE 
Figure l.-^The cell cycle. M = mitosis; Gi = post 
mitosis — pre-DNA synthesis period; S = DNA 
synthesis period; Gz = post DNA synthesis — pre- 
mitosis period; Go = potential dividers that may be 
stimulated to re-enter the generation cycle; ND = 
nondividers that are permanently incapable of di- 
viding. 
