The specific aims of the proposed research are to characterize the components of the extracellular matrix, and their interaction involved in the development and disposition of the connective tissue network in three animal models: 1) normal, neonatal development; 2) primary cultures of myocytes; and 3) certain disease models of hypertension where the heart undergoes hypertrophy. Biochemical techniques will be used to identify the type(s) of collagens and glycosaminoglycans present and to elaborate on the interaction of these components in the formation of the connective tissue network in vitro and in vivo. Histochemical techniques, including electron microscopy and immunochemistry using colloidal gold-labeled antibodies, will be used to localize these components. The collagen network functions physiologically in the distribution and transmission of the force generated by the contraction of myocytes, provides proper alignment of myocytes at rest length (mechanical coupling), and aids in maintaining capillary patency in the presence of high interventricular wall pressures. The connective tissue network of the left ventricle of the neonatal heart appears in the first 20 days postpartum. With tissue culture of neonatal myocytes, a collagen network is formed in cultures and collagen is associated with specific regions of the sarcolemma, as we have also shown in vivo. Using biochemical and histochemical techniques, we propose to determine the events involved in the formation of the connective tissue network and the manner of anchoring this network to the surfaces of myocytes. The connective tissue network increases in hearts undergoing pathological hypertrophy, and influences myocardial compliance. A similar analysis of the biochemical and histochemical events will be examined in the following models of hypertrophy: 1) genetic, spontaneous hypertensive rats (SHR); 2) rapid hypertrophy by aortic constriction; and 3) gradual hypertrophy in nephrectomized animals. These data will be correlated with data obtained from studies of normal developing hearts of neonates. Compliance measurements will be made on all three models of hypertrophy; data will be correlated with biochemical, histochemical, and morphological data to determine the effects of collagen and hypertrophy on compliance.
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