Medical
Hypotheses
4:
531-539,
1978
THE RELATIONSHIP OF HORMONES TO ARTERIAL GLYCOSAMINOGLYCANS AND ATHEROSCLEROSIS O.V. Sirek, E. Cukerman and A. Sirek. Department of Physiology and Division of Teaching Laboratories, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S lA8.
ABSTRACT Glycosaminoglycan fractions were measured in representative large and medium sized arteries of normal, hypophysectomized and hormone treated young beagles. Hyaluronate, heparan sulphate, dermatan sulphate and the isomeric chondroitin sulphates were determined in the aortic arch, thoracic and abdominal segments, in the external iliac, superior mesenteric, renal, common carotid and coronary arteries. The hormones used for replacement therapy of hypophysectomized animals were growth hormone, thyroxine, cortisone and the sex hormones testosterone, estrogen and progesterone. The sensitivity to an individual hormone was found to differ in various segments of the arterial tree; the thoracic and abdominal aorta were most responsive but renal and superior mesenteric arteries were relatively inert. The hypothesis is advanced that arteries with a GAG metabolism highly sensitive to hormones are more prone to develop atherosclerosis than arteries that have a limited sensitivity to alterations in endocrine balance. Key words:
Glycosaminoglycans Dogs
-
531
Arteries
-
Hormones
INTRODUCTION The arterial system as an endocrine target has received relatively little attention, and this is striking when compared with studies in adipose tissue or muscle. Also, the majority of experimental work was carried out on aortic tissue and it was tacitly assumed that the results were representative of the metabolic properties of the arterial tree in general. Already in our early studies we have found this assumption to be incorrect: the aortic arch responded to alterations in endocrine homeostasis, such as, hypophysectomy and replacement therapy with growth hormone or thyroxine, with fewer changes in composition than did the thoracic or abdominal portions of the aortic wall (1, 2). In these studies we measured the steady state concentrations of collagen, elastin, DNA and four fractions of the glycosaminoglycans (GAG): hyaluronic acid (HA), dermatan sulphate (DS), heparan sulphate (HS) and the isomeric chondroitin sulphates (CS). The differential sensitivity to hormones found within the three aortic segments made us consider the possibility that this may hold true also for other parts of the arterial system. Our study was therefore enlarged to include the external iliac, renal, superior mesenteric, common carotid, and coronary arteries. In addition to growth hormone, the effect of cortisone and each of the sex hormones testosterone, estradiol and progesterone were studied (3, 4, 5, 6 and unpublished observations). Chemical analysis was limited to GAG because particularly the sulphated variety was very sensitive to hormones. Female beagles 9 - 10 months of age were used in this investigation. Following hypophysectomy they were kept in the animal colony for eight weeks without replacement therapy and then for 3 weeks groups of animals were treated with one of the above mentioned hormones. At autopsy neither normal, nor hypophysectomized dogs with and without replacement therapy showed macroscopic alterations of their arterial walls. All vessels were cleaned of adventitia and GAG were extracted together from intima and media by conventional methods described elsewhere (5). Separation of GAG into individual fractions was done by electrophoresis. Even small vessels with a low GAG yield could be analyzed without the necessity of pooling. All canine vessels that we studied so far yielded four bands representing HA, HS, DS and CS.
EXPERIMENTAL DATA The purpose of this section is to provide an integrated picture of our findings and thereby provide the basis for our hypothesis to be presented below. Details of experimental data can be found
532
elsewhere
(1, 2, 3, 4, 5, 6, 7).
In general, multi-hormonal deficiency that ensues after hypophysectomy resulted in an overall reduction in the GAG content with the exception of the renal and superior mesenteric arteries which retained a normal GAG concentration. The reduction in total GAG content is not to be taken as an indication that all fractions were behaving in the same manner. The pattern of response of individual fractions varied from vessel to vessel in spite of similar reductions in total GAG content. Treatment of hypophysectomized dogs with a given hormone resulted in quantitative changes of the GAG content that were not uniform in the eight representative segments of the vascular tree. In other words, each vessel responded in a specific manner to hypophysectomy and to replacement with a given hormone, but the pattern of response differed in the various segments of the arterial system.
At this point it is difficult to understand the physiological significance of this differential sensitivity to hormones that we found in the various segments of the vascular tree.Nevertheless, its existence has clearly emerged under a variety of experimental conditions, and in order to bring the data on to a common denominator, we have attampted to give each arterial segment that we studied a numerical grade for its sensitivity to hormones (6). For reasons given below the sensitivity of each vessel was rated on a scale of 0 - 4. Calculations were based on total GAG content only, expressed as uranic acid in mg/g dried defatted tissue. When the reduction in the total GAG content in a given vessel was statistically significant (p< 0.05) after hypophysectomy, a value of 0.7 was assigned; if the reduction was only marginal The response to replace(P < O.l>, a value of 0.3 was assigned. ment treatment of hypophysectomized dogs with cortisone, growth hormone, and each of the three sex hormones (thyroxine studies are incomplete) was evaluated in a similar manner by assigning to statistically significant alterations a value of 0.7 and to marginal changes a value of 0.3. The sum of individual values so assigned gave a figure between 0 and 4 (4.2) the latter being the highest value for hormone sensitivity. The data on hormone sensitivity are given in conjunction with other results in Fig. 1. The fractional GAG content of eight segments of the normal canine arterial tree is presented and arranged in a descending order according to total uranic acid concentration. It will be noted that there is no close correlation between hormonal responsiveness (HR) and GAG content or elastin to collagen ratio (C/E). Nevertheless, with the exception of coronary arteries, it appears that muscular arteries in comparison to elastic arteries tend to have less GAG in their walls and the sensitivity to
533
hormones seems to be less prominent. Most of the values for coronary arteries are beyond the range found for other muscular arteries; the explanation may possibly lie in the unique hemodynamics prevailing in this part of the arterial system.
TOTAL GLYCOSAMINOGLYCAN CONTENT OF NORMAL CANINE ARTERJES
2.3
0.5
2.7
0.6
1.7
5.2
2.3
2.2
2.8
2.6
2.0
1.5
0.9
2.1
1.0
2.7
CIE-COLLAGENIELASTIN HR-HORMONAL RESPONSIVENESS
0
I
I
I
1
I
2
3
4
URONIC ACID
Fig. 1
mg/gDRY WEIGHT
Results of chemical analyses of 8 arterial segments of 10 months old normal beagles. Averages of 4 - 6 animals.
HYPOTHESIS
GAG, and particularly the sulphated variety are intimately associated with atherosclerosis (8, 9, 10, 11). Their ability to bind calcium ions, fibrinogen and particularly low density lipoproteins has been demonstrated in a number of laboratories and these properties appear to be more important than the mild anticoagulant activity ascribed to DS (12, 13, 14, 15, 16, 17, 18, 19, 20). The subject of GAG and atherosclerosis has been reviewed on a number of occasions (8, 9, 10) and it would be repetitious to go into detailed descriptions of their role in the formation of fatty streaks and plaques. Instead, we wish
534
tlES cs
M I
4.00
1 I_
EN.
CEREBRALS
, A”, c Madc c PO,I “.n I IIll ll111111
NON-CATASTROPHIC AGE 30-39 (20) Female (18) Male
3.00
l
----- .-e
2.50 .
2.00
iL! 0
1.50
1.00
.
4.00
OF II
,’
. ,*-’
L ,“.
x
/‘.,, ‘.,..
(’
.’
-8
OMMON ILlAt AORTA &II LI. *bdm li*bt WW UU
:?RQN;“R; MC II
,’
AE! CI IL
EN.
CERLBRALS
L Int. c Mid.c c P.,., v.n. I III1 II IIIIII NON-CATASTROPHIC AGE 40-49 (37) Female (24) Male *--------.
2.50
4 ., a,
: : i
*
Fig. 2a
Distribution of atherosclerotic lesions in human arteries graded on a 1 - 4 scale according to extent and severity (28). Reproduced Black dots were inserted by with the permission of the publishers. of corresponding canine arus indicating hormonal responsiveness Note the close correlation teries graded on the same scale. between these two parameters.
Fig, 2b
The same as 2a, but different age group.
535
to propose a hypothesis that is conceptually new in that it implies the existence of a relationship between the responsiveness of a given vascular segment to hormones and its susceptibility to atherosclerosis. In other words, the higher the sensitivity of a vascular segment to hormonal effects, the higher is the propensity to develop atherosclerosis. A search of the literature revealed that all mammals show some sort of degenerative lesions to occur in their vascular tree with age, although there is great variability in GAG composition, in susceptibility to damage and in the character of the lesions (21, 22, 23, 24, 25, 26, 27). On the other hand, the uneven distribution of lesions appears to be a common feature in all mammals, and so is the proliferation of intimal and/or medial muscle cells. Deposition of lipid material is a variable depending in part on the blood lipoprotein pattern of a particular species. In the dog, blood lipid levels are lower than in man and fatty streaks as well as irreversible accumulation of lipid in the arterial tree are not a dominant feature of canine degenerative vascular lesions (21, 23). We were unable to find a systematic study of the age dependent development of degenerative lesions in the various parts of the canine vascular tree. Investigations of this type were done repeatedly in man (28, 29, 30, 31, 32, 33). On the assumption that arteriosclerosis in its various forms is affecting all mammals, we have chosen to relate our data in dogs with the progression of atherosclerosis as it is described in humans. The investigation of Moses (28) was found to be most suitable for our purpose. Moses examined the histological appearance of the various segments of the human vascular tree and the atherosclerotic changes as they progressed from young to old age were graded on a scale from 1 to 4, the latter figure representing the most severe arterial lesions. Fig. 2a and 2b are reproduced from his book (28), showing the development of atherosclerotic lesions over two decades in males and females who came to autopsy for reasons other than death from cardiovascular disease. The heavy black dots were inserted by us and represent hormonal responsiveness (HR) in corresponding canine vessels. The positive correlation between hormonal responsiveness and susceptibility to atherosclerotic disease is striking. The carotid artery is not shown in Moses's scheme, but other investigators (32) have noted a high susceptibility to atherosclerosis which is in accord with our rating of 3.2 It is attractive to speculate that the positive correlation found between the degree of hormonal responsiveness in certain canine arterial segments and the propensity to develop degenerative lesions in corresponding human vessels is more than plain coincidence.
536
Our hypothesis is strengthened by the common knowledge that certain endocrine diseases, such as acromegaly, myxedema and diabetes are associated with a higher than normal incidence of cardiovascular complications (9, 34, 35).
ACKNOWLEDGMENTS Suported by Grants from the Ontario Heart Foundation, Medical Research Council of Canada (MA-6555) and Denison Mines Limited of Toronto. REFERENCES 1.
Brosnan ME. Effects of hypophysectomy, pancreatectomy and hormone replacement on the composition of canine aorta. (Thesis) University of Toronto. 1972.
2.
Brosnan ME, Sirek OV, Sirek A, Przybylska K. Action of growth hormone and thyroxine on aortas of hypophysectomized dogs. Diabetes 22: 243, 1973a.
3.
Sirek OV, Sirek A, Fikar K. Lack of somatotropin effect on glycosaminoglycan content of canine coronary arteries. Endocrinology 99: 1448, 1976.
4.
Sirek OV, Sirek A, Fikar K. The effect of sex hormones on glycosaminoglycan content of canine aorta and coronary arteries. Atherosclerosis 27: 227, 1977.
5.
Sirek OV, Sirek A, Cukerman E. Effect of hormones on the glycosaminoglycan content of canine renal arteries. Blood Vessels 15: 259, 1978.
6.
Fried V. The effect of hormones on the glycosaminoglycan content of canine arteries. (Thesis) University of Toronto. 1978.
7.
Brosnan ME, Sirek OV, Sirek A, Przybylska K. Effect of pancreatectomy with and without hypophysectomy and of insulin treatment on the composition of canine aorta, Diabetes 22: 397, 1973b.
8.
Berenson GS, Radhakrishnamurthy B, Dalferes ER, Srinivasan SR. Carbohydrate macromolecules and atherosclerosis. Human Pathology 2: 57, 1971.
9.
Berenson GS, Radhakrishnamurthy B, Srinivasan SR, Dalferes ER. Macromolecules in the arterial wall in relation to injury and repair a survey. Angiology 25: 649, 1974a.
10. Robinson RW, Likar IN,Likar LJ. Glycosaminoglycans in arterial disease. In monographs on Atherosclerosis, ~01.5. Eds. Kirk JE, Kritchevsky D Pollak OJ and Simms HS. Karger, Basel, 1975. il. Stevens RL, Colombo M, Gonzales JJ, Hollander W, Schmid K. The glycosaminoglycans of the human artery and their changes in atherosclerosis. J Clin Invest. 58: 470, 1976.
537
12. Kirk JE. Anticoagulant activity of human arterial mucopolysaccharides. Nature 184: 369, 1959. 13. Gore I, Larkey BJ. Functional activity of aortic mucopolysaccharides. J Lab Clin Med. 56: 839, 1960. 14. Amenta J, Waters L. The precipitation of serum lipoproteins by mucopolysaccharides extracted from aortic tissue. Yale J Biol Med. 33: 112, 1960. 15. Gero S, Gergely J, Devenyi T, et al. Role of intimal mucoid substances in pathogenesis of atherosclerosis. I. Complex formation in vitro between mucopolysaccharides from atherosclerotic intima and plasma -8- lipoprotein and fibrinogen. J Atheroscler Res. 1: 67, 1961. 16. Anderson AJ. The formation of chondromucoprotein-fibrinogen and chondromucoprotein -8- lipoprotein complexes; chemical and fibrinolytic properties. Biochem J. 88: 460, 1963. 17. Iverius P. The interactions between human plasma lipoproteins and connective tissue glycosaminoglycans. J Biol Chem. 247: 2607, 1972. 18. Srinivansan SR, Dolan P, Radhakrishnamurthy B, Berenson GS. Isolation of lipoprotein-acid mucopolysaccharide complexes from fatty streaks of human aorta. Prep Biochem.2: 83, 1972. 19..Bihari-Varga M, Gergely J, Gero S. Further investigations on complex formation in vitro between aortic mucopolysaccharides and B-lipoproteins. J Atheroscler Res. 4: 106, 1974. 20. Urist MR, Speer DP, Ibsen KJ, Sttates BS. sulfate. Tiss Res. 2: 253, 1968.
Calcium binding by chondroitin
21. Lindsay S, Chaikoff IL, Gilmore JW. Arteriosclerosis in the dog. 1. Spontaneous lesions in the aorta and the coronary arteries. AMA Archives of Pathology 53: 281, 1952. 22. Lindsay S, Feinberg H, Chaikoff IL, Entenman C, Reichert FL. Arteriosclerosis in the dog. 2. Aortic, cardiac and other vascular lesions inthymidectomized-hypophysectomized dogs. AMA Archives of Pathology 54: 573, 1952. 23. Dahme EG. Atherosclerosis and arteriosclerosis Ann NY Acad Sci.(USA). 127: 657, 1965. 24. Davies RF, Reinert H. Res. 5: 181, 1965.
Arteriosclerosis
in domestic animals.
in the young dog. J Atheroscler
25. Mullinger R, Manley G. Glycosaminoglycans and atherosclerosis in animal aortas. J Atheroscler Res. 9: 108, 1969. 26. Engel UR. Glycosaminoglycans sclerosis 13: 45, 1971.
in the aorta of six animal species. Athero-
27. Gardais A, Picard J, Hermelin B. Glycosaminoglycan distribution in aortic Comp Biochem Physiol. 44B: 507, 1973. wall from five species. . 28. Moses C. Atherosclerosis, p. 74, Lea and Febiger, Philadelphia, Pa; 1963, 29. Hatuki'F, Kirk JE. vascular.tissue.
Composition of acid mucopolysaccharides J Lab Clin Med. 64: 867, 1964.
538
in human
30. Manley G, Hawksworth J. Distribution of mucopolysaccharides human vascular tree. Nature 206: 1152, 1965.
in the
31. Mullinger WN, Manley G. Glycosaminoglycans and atheroma in the iliac arteries. J Atheroscler Res. 7: 401, 1967. 32. Nakamura M, Yabuta N. Difference in acid mucopolysaccharides contents among aortas, carotid and cerebral arteries. J Atheroscler Res. 7: 83, 1967. 33. Glagov S, Ozoa A. Significance of the relatively low incidence of atherosclerosis in the pulmonary, renal and mesenteric arteries. Ann NY Acad Sci.149: 940, 1968. 34. Knowles HC Jr. Control of diabetes and the progression of vascular In Diabetes Mellitus: Theory and Practice, pp.666-673 disease. (eds M Ellenberg, H Rifkin), New York: McGraw Hill Book Company 1970. In 35. Falsetti HL, Schnatz JD. Heart disease and diabetes mellitus. Diabetes Mellitus: Theory and Practice, pp. 870-889 (eds M Ellenberg, H Rifkin), New York: McGraw Hill Book Company 1970.
539
Hypotheses
4:
531-539,
1978
THE RELATIONSHIP OF HORMONES TO ARTERIAL GLYCOSAMINOGLYCANS AND ATHEROSCLEROSIS O.V. Sirek, E. Cukerman and A. Sirek. Department of Physiology and Division of Teaching Laboratories, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S lA8.
ABSTRACT Glycosaminoglycan fractions were measured in representative large and medium sized arteries of normal, hypophysectomized and hormone treated young beagles. Hyaluronate, heparan sulphate, dermatan sulphate and the isomeric chondroitin sulphates were determined in the aortic arch, thoracic and abdominal segments, in the external iliac, superior mesenteric, renal, common carotid and coronary arteries. The hormones used for replacement therapy of hypophysectomized animals were growth hormone, thyroxine, cortisone and the sex hormones testosterone, estrogen and progesterone. The sensitivity to an individual hormone was found to differ in various segments of the arterial tree; the thoracic and abdominal aorta were most responsive but renal and superior mesenteric arteries were relatively inert. The hypothesis is advanced that arteries with a GAG metabolism highly sensitive to hormones are more prone to develop atherosclerosis than arteries that have a limited sensitivity to alterations in endocrine balance. Key words:
Glycosaminoglycans Dogs
-
531
Arteries
-
Hormones
INTRODUCTION The arterial system as an endocrine target has received relatively little attention, and this is striking when compared with studies in adipose tissue or muscle. Also, the majority of experimental work was carried out on aortic tissue and it was tacitly assumed that the results were representative of the metabolic properties of the arterial tree in general. Already in our early studies we have found this assumption to be incorrect: the aortic arch responded to alterations in endocrine homeostasis, such as, hypophysectomy and replacement therapy with growth hormone or thyroxine, with fewer changes in composition than did the thoracic or abdominal portions of the aortic wall (1, 2). In these studies we measured the steady state concentrations of collagen, elastin, DNA and four fractions of the glycosaminoglycans (GAG): hyaluronic acid (HA), dermatan sulphate (DS), heparan sulphate (HS) and the isomeric chondroitin sulphates (CS). The differential sensitivity to hormones found within the three aortic segments made us consider the possibility that this may hold true also for other parts of the arterial system. Our study was therefore enlarged to include the external iliac, renal, superior mesenteric, common carotid, and coronary arteries. In addition to growth hormone, the effect of cortisone and each of the sex hormones testosterone, estradiol and progesterone were studied (3, 4, 5, 6 and unpublished observations). Chemical analysis was limited to GAG because particularly the sulphated variety was very sensitive to hormones. Female beagles 9 - 10 months of age were used in this investigation. Following hypophysectomy they were kept in the animal colony for eight weeks without replacement therapy and then for 3 weeks groups of animals were treated with one of the above mentioned hormones. At autopsy neither normal, nor hypophysectomized dogs with and without replacement therapy showed macroscopic alterations of their arterial walls. All vessels were cleaned of adventitia and GAG were extracted together from intima and media by conventional methods described elsewhere (5). Separation of GAG into individual fractions was done by electrophoresis. Even small vessels with a low GAG yield could be analyzed without the necessity of pooling. All canine vessels that we studied so far yielded four bands representing HA, HS, DS and CS.
EXPERIMENTAL DATA The purpose of this section is to provide an integrated picture of our findings and thereby provide the basis for our hypothesis to be presented below. Details of experimental data can be found
532
elsewhere
(1, 2, 3, 4, 5, 6, 7).
In general, multi-hormonal deficiency that ensues after hypophysectomy resulted in an overall reduction in the GAG content with the exception of the renal and superior mesenteric arteries which retained a normal GAG concentration. The reduction in total GAG content is not to be taken as an indication that all fractions were behaving in the same manner. The pattern of response of individual fractions varied from vessel to vessel in spite of similar reductions in total GAG content. Treatment of hypophysectomized dogs with a given hormone resulted in quantitative changes of the GAG content that were not uniform in the eight representative segments of the vascular tree. In other words, each vessel responded in a specific manner to hypophysectomy and to replacement with a given hormone, but the pattern of response differed in the various segments of the arterial system.
At this point it is difficult to understand the physiological significance of this differential sensitivity to hormones that we found in the various segments of the vascular tree.Nevertheless, its existence has clearly emerged under a variety of experimental conditions, and in order to bring the data on to a common denominator, we have attampted to give each arterial segment that we studied a numerical grade for its sensitivity to hormones (6). For reasons given below the sensitivity of each vessel was rated on a scale of 0 - 4. Calculations were based on total GAG content only, expressed as uranic acid in mg/g dried defatted tissue. When the reduction in the total GAG content in a given vessel was statistically significant (p< 0.05) after hypophysectomy, a value of 0.7 was assigned; if the reduction was only marginal The response to replace(P < O.l>, a value of 0.3 was assigned. ment treatment of hypophysectomized dogs with cortisone, growth hormone, and each of the three sex hormones (thyroxine studies are incomplete) was evaluated in a similar manner by assigning to statistically significant alterations a value of 0.7 and to marginal changes a value of 0.3. The sum of individual values so assigned gave a figure between 0 and 4 (4.2) the latter being the highest value for hormone sensitivity. The data on hormone sensitivity are given in conjunction with other results in Fig. 1. The fractional GAG content of eight segments of the normal canine arterial tree is presented and arranged in a descending order according to total uranic acid concentration. It will be noted that there is no close correlation between hormonal responsiveness (HR) and GAG content or elastin to collagen ratio (C/E). Nevertheless, with the exception of coronary arteries, it appears that muscular arteries in comparison to elastic arteries tend to have less GAG in their walls and the sensitivity to
533
hormones seems to be less prominent. Most of the values for coronary arteries are beyond the range found for other muscular arteries; the explanation may possibly lie in the unique hemodynamics prevailing in this part of the arterial system.
TOTAL GLYCOSAMINOGLYCAN CONTENT OF NORMAL CANINE ARTERJES
2.3
0.5
2.7
0.6
1.7
5.2
2.3
2.2
2.8
2.6
2.0
1.5
0.9
2.1
1.0
2.7
CIE-COLLAGENIELASTIN HR-HORMONAL RESPONSIVENESS
0
I
I
I
1
I
2
3
4
URONIC ACID
Fig. 1
mg/gDRY WEIGHT
Results of chemical analyses of 8 arterial segments of 10 months old normal beagles. Averages of 4 - 6 animals.
HYPOTHESIS
GAG, and particularly the sulphated variety are intimately associated with atherosclerosis (8, 9, 10, 11). Their ability to bind calcium ions, fibrinogen and particularly low density lipoproteins has been demonstrated in a number of laboratories and these properties appear to be more important than the mild anticoagulant activity ascribed to DS (12, 13, 14, 15, 16, 17, 18, 19, 20). The subject of GAG and atherosclerosis has been reviewed on a number of occasions (8, 9, 10) and it would be repetitious to go into detailed descriptions of their role in the formation of fatty streaks and plaques. Instead, we wish
534
tlES cs
M I
4.00
1 I_
EN.
CEREBRALS
, A”, c Madc c PO,I “.n I IIll ll111111
NON-CATASTROPHIC AGE 30-39 (20) Female (18) Male
3.00
l
----- .-e
2.50 .
2.00
iL! 0
1.50
1.00
.
4.00
OF II
,’
. ,*-’
L ,“.
x
/‘.,, ‘.,..
(’
.’
-8
OMMON ILlAt AORTA &II LI. *bdm li*bt WW UU
:?RQN;“R; MC II
,’
AE! CI IL
EN.
CERLBRALS
L Int. c Mid.c c P.,., v.n. I III1 II IIIIII NON-CATASTROPHIC AGE 40-49 (37) Female (24) Male *--------.
2.50
4 ., a,
: : i
*
Fig. 2a
Distribution of atherosclerotic lesions in human arteries graded on a 1 - 4 scale according to extent and severity (28). Reproduced Black dots were inserted by with the permission of the publishers. of corresponding canine arus indicating hormonal responsiveness Note the close correlation teries graded on the same scale. between these two parameters.
Fig, 2b
The same as 2a, but different age group.
535
to propose a hypothesis that is conceptually new in that it implies the existence of a relationship between the responsiveness of a given vascular segment to hormones and its susceptibility to atherosclerosis. In other words, the higher the sensitivity of a vascular segment to hormonal effects, the higher is the propensity to develop atherosclerosis. A search of the literature revealed that all mammals show some sort of degenerative lesions to occur in their vascular tree with age, although there is great variability in GAG composition, in susceptibility to damage and in the character of the lesions (21, 22, 23, 24, 25, 26, 27). On the other hand, the uneven distribution of lesions appears to be a common feature in all mammals, and so is the proliferation of intimal and/or medial muscle cells. Deposition of lipid material is a variable depending in part on the blood lipoprotein pattern of a particular species. In the dog, blood lipid levels are lower than in man and fatty streaks as well as irreversible accumulation of lipid in the arterial tree are not a dominant feature of canine degenerative vascular lesions (21, 23). We were unable to find a systematic study of the age dependent development of degenerative lesions in the various parts of the canine vascular tree. Investigations of this type were done repeatedly in man (28, 29, 30, 31, 32, 33). On the assumption that arteriosclerosis in its various forms is affecting all mammals, we have chosen to relate our data in dogs with the progression of atherosclerosis as it is described in humans. The investigation of Moses (28) was found to be most suitable for our purpose. Moses examined the histological appearance of the various segments of the human vascular tree and the atherosclerotic changes as they progressed from young to old age were graded on a scale from 1 to 4, the latter figure representing the most severe arterial lesions. Fig. 2a and 2b are reproduced from his book (28), showing the development of atherosclerotic lesions over two decades in males and females who came to autopsy for reasons other than death from cardiovascular disease. The heavy black dots were inserted by us and represent hormonal responsiveness (HR) in corresponding canine vessels. The positive correlation between hormonal responsiveness and susceptibility to atherosclerotic disease is striking. The carotid artery is not shown in Moses's scheme, but other investigators (32) have noted a high susceptibility to atherosclerosis which is in accord with our rating of 3.2 It is attractive to speculate that the positive correlation found between the degree of hormonal responsiveness in certain canine arterial segments and the propensity to develop degenerative lesions in corresponding human vessels is more than plain coincidence.
536
Our hypothesis is strengthened by the common knowledge that certain endocrine diseases, such as acromegaly, myxedema and diabetes are associated with a higher than normal incidence of cardiovascular complications (9, 34, 35).
ACKNOWLEDGMENTS Suported by Grants from the Ontario Heart Foundation, Medical Research Council of Canada (MA-6555) and Denison Mines Limited of Toronto. REFERENCES 1.
Brosnan ME. Effects of hypophysectomy, pancreatectomy and hormone replacement on the composition of canine aorta. (Thesis) University of Toronto. 1972.
2.
Brosnan ME, Sirek OV, Sirek A, Przybylska K. Action of growth hormone and thyroxine on aortas of hypophysectomized dogs. Diabetes 22: 243, 1973a.
3.
Sirek OV, Sirek A, Fikar K. Lack of somatotropin effect on glycosaminoglycan content of canine coronary arteries. Endocrinology 99: 1448, 1976.
4.
Sirek OV, Sirek A, Fikar K. The effect of sex hormones on glycosaminoglycan content of canine aorta and coronary arteries. Atherosclerosis 27: 227, 1977.
5.
Sirek OV, Sirek A, Cukerman E. Effect of hormones on the glycosaminoglycan content of canine renal arteries. Blood Vessels 15: 259, 1978.
6.
Fried V. The effect of hormones on the glycosaminoglycan content of canine arteries. (Thesis) University of Toronto. 1978.
7.
Brosnan ME, Sirek OV, Sirek A, Przybylska K. Effect of pancreatectomy with and without hypophysectomy and of insulin treatment on the composition of canine aorta, Diabetes 22: 397, 1973b.
8.
Berenson GS, Radhakrishnamurthy B, Dalferes ER, Srinivasan SR. Carbohydrate macromolecules and atherosclerosis. Human Pathology 2: 57, 1971.
9.
Berenson GS, Radhakrishnamurthy B, Srinivasan SR, Dalferes ER. Macromolecules in the arterial wall in relation to injury and repair a survey. Angiology 25: 649, 1974a.
10. Robinson RW, Likar IN,Likar LJ. Glycosaminoglycans in arterial disease. In monographs on Atherosclerosis, ~01.5. Eds. Kirk JE, Kritchevsky D Pollak OJ and Simms HS. Karger, Basel, 1975. il. Stevens RL, Colombo M, Gonzales JJ, Hollander W, Schmid K. The glycosaminoglycans of the human artery and their changes in atherosclerosis. J Clin Invest. 58: 470, 1976.
537
12. Kirk JE. Anticoagulant activity of human arterial mucopolysaccharides. Nature 184: 369, 1959. 13. Gore I, Larkey BJ. Functional activity of aortic mucopolysaccharides. J Lab Clin Med. 56: 839, 1960. 14. Amenta J, Waters L. The precipitation of serum lipoproteins by mucopolysaccharides extracted from aortic tissue. Yale J Biol Med. 33: 112, 1960. 15. Gero S, Gergely J, Devenyi T, et al. Role of intimal mucoid substances in pathogenesis of atherosclerosis. I. Complex formation in vitro between mucopolysaccharides from atherosclerotic intima and plasma -8- lipoprotein and fibrinogen. J Atheroscler Res. 1: 67, 1961. 16. Anderson AJ. The formation of chondromucoprotein-fibrinogen and chondromucoprotein -8- lipoprotein complexes; chemical and fibrinolytic properties. Biochem J. 88: 460, 1963. 17. Iverius P. The interactions between human plasma lipoproteins and connective tissue glycosaminoglycans. J Biol Chem. 247: 2607, 1972. 18. Srinivansan SR, Dolan P, Radhakrishnamurthy B, Berenson GS. Isolation of lipoprotein-acid mucopolysaccharide complexes from fatty streaks of human aorta. Prep Biochem.2: 83, 1972. 19..Bihari-Varga M, Gergely J, Gero S. Further investigations on complex formation in vitro between aortic mucopolysaccharides and B-lipoproteins. J Atheroscler Res. 4: 106, 1974. 20. Urist MR, Speer DP, Ibsen KJ, Sttates BS. sulfate. Tiss Res. 2: 253, 1968.
Calcium binding by chondroitin
21. Lindsay S, Chaikoff IL, Gilmore JW. Arteriosclerosis in the dog. 1. Spontaneous lesions in the aorta and the coronary arteries. AMA Archives of Pathology 53: 281, 1952. 22. Lindsay S, Feinberg H, Chaikoff IL, Entenman C, Reichert FL. Arteriosclerosis in the dog. 2. Aortic, cardiac and other vascular lesions inthymidectomized-hypophysectomized dogs. AMA Archives of Pathology 54: 573, 1952. 23. Dahme EG. Atherosclerosis and arteriosclerosis Ann NY Acad Sci.(USA). 127: 657, 1965. 24. Davies RF, Reinert H. Res. 5: 181, 1965.
Arteriosclerosis
in domestic animals.
in the young dog. J Atheroscler
25. Mullinger R, Manley G. Glycosaminoglycans and atherosclerosis in animal aortas. J Atheroscler Res. 9: 108, 1969. 26. Engel UR. Glycosaminoglycans sclerosis 13: 45, 1971.
in the aorta of six animal species. Athero-
27. Gardais A, Picard J, Hermelin B. Glycosaminoglycan distribution in aortic Comp Biochem Physiol. 44B: 507, 1973. wall from five species. . 28. Moses C. Atherosclerosis, p. 74, Lea and Febiger, Philadelphia, Pa; 1963, 29. Hatuki'F, Kirk JE. vascular.tissue.
Composition of acid mucopolysaccharides J Lab Clin Med. 64: 867, 1964.
538
in human
30. Manley G, Hawksworth J. Distribution of mucopolysaccharides human vascular tree. Nature 206: 1152, 1965.
in the
31. Mullinger WN, Manley G. Glycosaminoglycans and atheroma in the iliac arteries. J Atheroscler Res. 7: 401, 1967. 32. Nakamura M, Yabuta N. Difference in acid mucopolysaccharides contents among aortas, carotid and cerebral arteries. J Atheroscler Res. 7: 83, 1967. 33. Glagov S, Ozoa A. Significance of the relatively low incidence of atherosclerosis in the pulmonary, renal and mesenteric arteries. Ann NY Acad Sci.149: 940, 1968. 34. Knowles HC Jr. Control of diabetes and the progression of vascular In Diabetes Mellitus: Theory and Practice, pp.666-673 disease. (eds M Ellenberg, H Rifkin), New York: McGraw Hill Book Company 1970. In 35. Falsetti HL, Schnatz JD. Heart disease and diabetes mellitus. Diabetes Mellitus: Theory and Practice, pp. 870-889 (eds M Ellenberg, H Rifkin), New York: McGraw Hill Book Company 1970.
539
