ENDOTHELIAL CELL GROWTH FACTORS

Abstract

The endothelium, which lines the major vessels of the cardiovascular system and forms the capillary networks, plays a primary role in many vital physiologic processes including nutrient transport, immune function, coagulation, hormone metabolism and vasomotor control. An in vitro model system consisting of cultured endothelial monolayers has enhanced our ability to investigate the biochemical mechanisms underlying endothelial cell function, including the regulation of endothelial cell growth.;Isolated human umbilical vein, aortic or capillary endothelial cells exhibit a strict requirement for one of several growth factors that promote survival and proliferation of the endothelial cells. We have identified, purified and characterized three growth factors which allow human endothelial cells to be serially propagated in vitro. Two of the proteins, endothelial cell growth factor I and II (ECGF I and ECGF II), isolated from human or bovine brain, exhibit high affinity binding to the glycosaminoglycan heparin and are active mitogens in vitro at concentrations of 100 pg/ml. The complete amino acid sequences of the proteins have been determined: The proteins are 55% homologous, are distantly related to interleukin 1{dollar}\beta{dollar} and contain internal neuropeptide-like sequences flanked by potential proteolytic processing sites. The molecular weights of ECGF I, pI 5.2, and ECGF II, pI 9.5, are 16,000 and 17,000 respectively. ECGF modulates both endothelial cell adhesion and the production and deposition of glycosaminoglycans by the endothelium, increasing the levels of chondroitins and hyaluronic acid while inhibiting the production of heparan sulfates. A third endothelial cell mitogen has been purified 4,000 fold from the serum free medium conditioned by a cell line derived from a rat glioma. The 20,000 dalton protein, which is an active mitogen for endothelial cells in vitro at 1 ng/ml, exhibits no specific binding to heparin. It is a cationic protein with an apparent p I of 8.5 and like ECGF II, is also a potent stimulator of neurite outgrowth in cultured neuronal cells.