Date of Award
Doctor of Philosophy
O.G. Hall, J.T. Miles
Vitamin A is one of the earliest essential vitamins discovered, and so far attempts have failed to uncover its specific mode of action within the living animal. Its role in vision is best known and has been elucidated by Wald (1955), but in addition, vitamin A has other important metabolic functions that are less well understood. For example, an animal may die from vitamin A deficiency in the absence of any apparent eye damage. Morphological changes caused by a deficiency of this vitamin, such as epithelial keratinization (Wolbach and Howe, 1925), have been studied extensively. There has been a considerable amount of investigation in recent years into the action of vitamin A at the molecular level, but much remains to be deciphered. Nevertheless, it is apparent that vitamin A has an important influence on mucopolysaccharide (MPS) biosynthesis (Fell, Mellanby and Pelc, 1954; Dziewiatkowski, 1954; Wolf and Varandani, 1960; Varandani, Wolf and Johnson, 1960; Wolf, Bergan and Sundaresan, 1962; Wolf, Bergan and Sundaresan, 1963).
Deficiency of vitamin A results in a decrease in the number and activity of cells in all epithelial tissues that secrete mucus--cells in the respiratory (Wolbach and Howe, 1925), intestinal (Gross, 1924; Richards 1935), and urinary tracts and the genital system (Moore, 1957)--and of cells in other tissues where MPS is synthesized, especially in cartilage. It has been shown that uptake of 35SO4 into chondroitin sulfates of cartilage is reduced in the vitamin A-deficient mammal, a result suggesting a decreased synthesis of MPS (Dziewiatkowski, 1954). Excess vitamin A, on the other hand, results in accelerated maturation of cartilage cells (Fell and Mellanby, 1953) and the mucoprotein (a mucopolysaccharide-protein complex) levels of the blood are greatly increased (Cohen, Maddock and Wolbach, 1955; Thomas et al., 1960). Toxic levels of vitamin A adversely affect the same tissues—reproductive organs (Maddock, Cohen and Wolbach, 1953; bones (Clark and Smith, 1964;); skin (Chung and Houck, 1964; Barker, Cruickshank and Webb, 1964); and articular and epiphyseal cartilage matrix (McElligott, 1962; Clark and Smith, 1964)--apparently to some extent by interfering with normal MPS biosynthesis. Vitamin A has a direct action, possibly coenzymatic, on the polymerization of uridine nucleotides to form MPS or on the sulfonation of MPS (Wolf and Varandani, 1960).
In addition to altered MPS biosynthesis, hemorrhages are commonly associated both with deficiency and excess of vitamin A (Frank, 1934) Rodahl and Moore, 1943; Rodahl, 1950; Richardson, 1961), and are believed to be a cause of death associated with this vitamin (Maddock, Wolbach and Jensen, 1948). Blood platelets are involved in prevention of hemorrhages and have MPS as one of their components (Odell and Anderson, 1957; Anderson and Odell, 1958; Kerby and Taylor, 1959; Odell and McDonald, 1964a).
Of the three hemostasis-producing roles of blood platelets commonly listed [(1) clumping and fusing of the platelets at the site of blood vessel injury, (2) clotting, and (3) maintaining the resistance of the capillaries to red cell extravasation, the least understood is its role in maintaining the integrity of the capillaries (Zucker and Borrelli, 1958). Vitamin A has also long been known to be involved in maintaining the integrity of certain specialized epithelial tissues. Of these tissues, the capillary endothelium (Rodahl, 1950) is the one most commonly associated with vitamin A deficiency, a condition leading to capillary fragility and hemorrhages.
Since blood platelets contain MPS and vitamin A has already been demonstrated to control MPS biosynthesis, it seems possible that an excess or deficiency of vitamin A may affect the synthesis of mucopolysaccharides within blood platelets. MPS compounds of various kinds have been linked both to the coagulation process and to anti-coagulation and may be among the constituents of platelets responsible for their hemostatic effect. Therefore, since both blood platelets and vitamin A are known to be involved in maintenance of the integrity of the capillary endothelium, the influence of vitamin A on capillary endothelium may be indirect by way of its effect on MPS synthesis in blood platelets.
The objective of this research problem was to study the effects of vitamin A on peripheral blood platelets, platelet MPS, and other hematologic factors. Blood platelets were compared from vitamin Atreated rats, rats fed a normal diet, a vitamin A-deficient diet, or a vitamin A-deficient diet with vitamin A added. The specific objectives of this investigation were to determine in these groups of rats:
1. Peripheral cell numbers of blood platelets, white blood cells, red blood cells as well as hematocrits and body weights.
2. Relative sizes of blood platelets.
3. Incorporation of 35S-Sulfate into blood platelets and plasma.
4.. Hexosamine and protein content of blood platelets.
5. Relative amounts of several mucopolysaccharides in blood platelets (chondroitin sulfates A, B, and C, and heparin).
6. Adhesiveness of blood platelets.
McDonald, Ted Painter, "An investigation of the effects of vitamin A on mucopolysaccharides of rat blood platelets. " PhD diss., University of Tennessee, 1965.