Butt, Richard Philip; (1996) Effect of mechanical load and polypeptide growth factors on cardiovascular fibroblast function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cells of the cardiovascular system are constantly subjected to mechanical forces during the cardiac cycle. These forces are increased due to physiological and pathological disorders resulting in remodelling of the tissues in order to withstand the increased pressure. One aspect of the remodelling process involves increased deposition of the extracellular matrix (ECM) protein collagen and replication of the fibroblast population, the major collagen-producing cells of the cardiovascular system. The mechanisms regulating increased fibroblast collagen deposition are poorly characterized. An in vitro cell straining device (Flexercell FX2000) has been used in this study to determine the direct effects of mechanical load on primary cultures of both cardiac and pulmonary artery fibroblasts. The effect of mechanical load and polypeptide growth factors on fibroblast procollagen protein metabolism, steady state procollagen raRNA levels and fibroblast replication was determined. It was found that mechanical load alone had no effect on either cardiac or arterial fibroblast collagen metabolism. However, in combination with a stimulation by 10% foetal calf serum (FCS), mechanical load produced a highly significant, synergistic stimulation of both procollagen metabolism and steady state type I and type III procollagen mRNA levels. Furthermore, polypeptide growth factors known to be present in the remodelling heart and vessels were demonstrated to stimulate fibroblast procollagen metabolism, and the effects of these growth factors were also enhanced by mechanical load. Fibroblast replication was stimulated by some of the growth factors tested, although mechanical load had no effect either alone or in combination with these factors. These results demonstrate that serum factors and specific polypeptide growth factors stimulate cardiac and pulmonary artery fibroblast procollagen metabolism and replication, and that mechanical load enhances these effects on procollagen gene expression and metabolism. This mechanism represents a novel pathway whereby mechanical load and growth factors act synergistically to stimulate increased fibroblast procollagen metabolism.

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