Atherosclerosis and Arteriosclerosis

Rodney A. White

• Publisher: CRC Press
• Year: 2019
• ISBN:
  9781000722390
• Edition: 1
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

Selected as an outstanding book in vascular surgery by members of the Society for Vascular Surgery.*This unique new text describes the current understanding of the etiology and pathogenesis of human atherosclerosis. It also details the methods for quantitating and characterizing both experimental and clinical lesions, and describes the methods for preparing available animal models. Providing an in-depth review of each of these topics, the text organizes the information in one volume for the convenience of the reader. The text is divided into two sections. First is a description of the cell biology, biochemistry and pharmacology of normal vessels and of atherosclerotic human lesions, with details of the methods to accurately characterize and quantitate the disease. Secondly, it presents a description of the methods for preparing the available experimental animal models, including a discussion of the distribution and pathological characteristics of the lesions. It also includes comparisons of human atherosclerosis and experimental animal models. Intended to provide a basis for expediting future research in this priority health care area, this text compiles the available information for those who treat patients with atherosclerosis or who are involved in atherosclerosis research. It is of particular interest to students, physicians, and academic and commercial researchers.

Animal Models of Atherosclerosis

Chapter 6

ATHEROSCLEROSIS IN PIGEONS

Bill C. Bullock

Many types of birds either have naturally occurring atherosclerosis or are susceptible to diet-induced atherosclerosis. Pigeons have been used extensively in atherosclerosis research and this review will be limited to work done with pigeons.

There are many breeds and strains of pigeons. Pigeon fanciers have selected birds for many different characteristics.¹ Among the pigeons most often used in atherosclerosis research are the White Carneau (WC) and the Show Racer (SR) breeds with some selection of strains within these breeds.

The WC breed was developed by Levi at the Palmetto Pigeon Plant, Sumpter, S.C. A few pairs of birds formed the foundation of this breed.¹ The breeding colony at the Bowman Gray School of Medicine of Wake Forest University is possibly the sole colony of “pure” WC since White King genes have been introduced into the Palmetto WC. The Show Racer pigeons are more heterogeneous and were also developed at PPP.

Interest in pigeons at this institution began in the late 1950s. Among the several breeds of pigeons examined, the WC and SR were settled upon as the subjects of continued investigation.^2,3

The WC develops naturally occurring atherosclerosis in the thoracic aorta just proximal to the origin of the coeliac artery.

The natural history of atherosclerosis in WC and SR has been described by Prichard et al.^3,4 Well-illustrated reviews are provided in Roberts and Strauss.⁵

SR pigeons are relatively resistant to both naturally occurring and diet-induced aortic atherosclerosis. This breed is not resistant to diet-induced coronary atherosclerosis. Myocardial infarction occurs in pigeons with complicated atherosclerotic lesions. Some of these infarcts are caused by embolization of calcific material from the aortic root.⁶

Aortic atherosclerosis of WC and SR has been the subject of many investigations. Total plasma cholesterol concentrations do not differ between WC and SR when the birds are fed cholesterol-free grain-based diets. The two breeds respond to dietary cholesterol in virtually the same way. These statements must be tempered by the relative paucity of data on pigeon apolipoproteins. The presence of apo B and apo Al is well established, but the other apoproteins have not been completely characterized. The pigeon does not appear to have apo E, and if a functionally similar apoprotein exists, it has not yet been described.⁷

Most investigations have assumed plasma lipids to be the same between the two breeds. Although the SR is equally susceptible to diet-induced coronary artery atherosclerosis, the breed difference at the spot in the aorta where WC develop naturally occurring lesions is maintained. The characteristics of the lesions induced or aggravated by diet are changed, there being more macrophages, but the difference in lesion size is maintained.

The lack of demonstrated differences in plasma lipids has prompted a number of experiments directed at differences in arterial metabolism.⁸ Among the differences found are that WC aorta derived more energy from glycolysis than SR. There is relatively more cholesterol esterification and less cholesteryl ester hydrolysis among WC than SR. Pigeon smooth muscle cells lack low density lipoprotein receptors, and accumulate very little lipid under cell culture conditions.⁹ Pigeon macrophages accumulate large amounts of cholesteryl esters when β migrating very low density lipoprotein (the major plasma lipid that is elevated in cholesterol-fed pigeons) is added to the culture medium. There is increased adherence of blood cells (monocytes and thrombocytes) and increased endothelial cell turnover in developing lesions.¹⁰ Avian red blood cells and thrombocytes are nucleated cells, but are functionally quite similar to the mammalian counterparts. Pigeon thrombocyte adhesion to glass is inhibited by LDL¹¹ possibly by modulation of cyclic AMP.¹² Fibrinogen binding to thrombocytes occurs when the thrombocytes are activated by either aggregation or adhesion. The binding sites differ depending on the activating stimulus.¹³

The well-documented time course and lesion production site of WC pigeons has led to some elegant correlative morphological studies. Endothelial cell proliferation and monocyte adhesion is greatest at the developing edge of lesions¹⁰ as is accumulation of radiolabeled LDL determined by electron microscopic autoradiography.¹⁴ Monocyte chemoattractants have been found in extracts of aortic lesions of pigeons.¹⁵

Arteries are basically connective tissue and some primary components of connective tissue are proteoglycans (PG). Proteoglycan synthesis and degradation are inherent responses of connective tissues to local environmental conditions. Dermatan sulfate content is increased in atherosclerotic arteries, and LDL complexes more readily to dermatan sulfate than some other glycoproteins.

The WC-2 strain was selected for more extensive atherosclerosis from the random bred colony of WC (RBWC).¹⁶ Although no difference has been described in the lipoproteins from RBWC vs WC2 or SR more WC2 lipoprotein is complexed when plasma from the WC2 and RBWC is added to the same proteoglycan mixture. In crossover experiments SR lipoproteins bind to the PG mixture from either breed but the greatest binding was WC lipoprotein with WC proteoglycan.^17,18

Dermatan sulfate proteoglycan (DSPG) concentration increases with atherosclerosis in several species including people and pigeons. WC-2 DSPG differs from that of RBWC even in 18-d embryos.¹⁹ The core proteins seem to be similar but the DSPG monomers are of different sizes (WC-2 MW = 15,000; RBWC = 18,000). Differences in proteoglycan synthesis and degradation between WC and SR arterial smooth muscle cells result in higher dermatan sulfate to chondroitin sulfate ratios in the WC cultures. This difference was due to increased degradation of chondroitin sulfate by the WC cells.²⁰ There are other differences between WC and SR. Aortic smooth muscle cells from WC grown in tissue culture systems are smaller than SR cells in the same kind of system.²⁰

These findings indicate that there are components of susceptibility and resistance to atherosclerosis associated with both plasma and tissue.

Pigeon LDL size increases when the birds are fed a cholesterol-containing diet and there is an association between LDL and size and aortic atherosclerosis. Although the SR LDL size increase is as much or more than the WC LDL size increase, WC still have the most extensive aortic atherosclerosis. Among WC pigeons whose LDL size was relatively low, there was a better relationship between atherosclerosis and LDL binding to proteoglycan than between atherosclerosis and LDL size. The number of particles bound actually decreased as LDL size increased, possibly due to stearic hindrance. The amount of cholesterol present in the bound substance was increased due to the increased amount of cholesteryl ester in the core of large particles.²¹

There are no differences in blood pressure between WC and SR or between RBWC and WC-2 to account for the differences in extent and severity of atherosclerosis among the various strains of pigeons. It is possible, however, to select for differences in blood pressure within strains. WC of the high blood pressure (HBP) line have lower compliance of the aorta than birds of the low blood pressure (LBP) at 6 months of age. When the pigeons are fed a low (0.1% W/W) cholesterol diet, HBP have more atherosclerosis than LBP. This combination of naturally occurring atherosclerosis and hypertension provides a unique animal model for the study of cardiovascular disease. The differences in blood pressure are measurable when the pigeons are quite young (1 month) before arterial stiffening due to atherosclerosis could have any effect on blood pressure.²² Advanced atherosclerosis is associated with increased blood pressure in RBWC.²³

Pigeons are relatively inexpensive to obtain and maintain, and a breeding pair can produce from 6 to 12 offspring per year.²⁴ Susceptibility to atherosclerosis and hypertension can be selected for and the application of the techniques of molecular genetic...

Table of contents

• Cover
• Title Page
• Copyright Page
• DEDICATION
• ACKNOWLEDGMENTS
• PREFACE
• THE EDITOR
• CONTRIBUTORS
• Table of Contents
• THE HUMAN ATHEROSCLEROTIC LESION
• QUANTITATIVE ASSESSMENT OF ARTERIAL WALL COMPONENTS
• ANIMAL MODELS OF ATHEROSCLEROSIS
• VASCULAR GRAFT PATHOLOGY
• FUTURE PERSPECTIVES
• INDEX