Endocytosis is involved in the metabolism of blood-borne macromolecules by both vascular endothelium and smooth muscle cells (SMC). Intimal SMC proliferation is a prominent feature of atherogenesis and therefore the interactions between the cell cycle, growth factors and endocytosis are relevant to this disease process. Manipulation of the growth of smooth muscle cells in culture by platelet- derived growth factor (PDGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) has demonstrated a coupling between endocytic volume (fluid endocytosis), endocytosis of low density lipoproteins (LDL) and growth regulation. Fluid endocytosis rate increased up to 10 fold per responding cell early in the cell cycle and continued elevated through S phase before declining. The magnitude of the effect was proportional to the fraction of cells entering the cycle, and when density-dependent inhibition of growth occurred, it was accompanied by density-dependent inhibition of fluid endocytosis rate. In addition to these changes in rate of fluid endocytosis, we also studied the high affinity binding, endocytosis and degradation of LDL. PDGF and FGF stimulated LDL binding by up to 300% and this also resulted in enhanced LDL degradation. Removal of growth factor after initiation of the cell cycle, however, abolished the response, suggesting that the continued presence of growth factor was required for enhanced LDL binding.A direct relationship between fluid endocytosis and cell growth was also measured in cultured endothelium, but exposure of confluent endothelium to PDGF or FGF resulted in increased binding of LDL without a growth response.These results, together with the failure to enhance binding of LDL to cycling SMC after removal of mitogen, suggest that growth factor stimulation of LDL binding and its consequences may be uncoupled from cell growth even though the common carrier for internalisation (endocytic vesicle volume) is closely related to the cell cycle.
A Redox Signaling Mechanism for Density-dependent Inhibition of Cell Growth