Early Response Genes in Endothelial Cells

Summary

The vascular endothelial cells initiate angiogenesis when stimulated by growth factors and cytokines. While the cellular activities of the angiogenic factors such as the fibroblast growth factors (FGF), tumor necrosis factor (TNFα) and type-β transforming growth factor are well-characterized, molecular mechanisms involved in the different phases of angiogenesis, namely, migration, proliferation and differentiation are not well-understood. Protein kinase-C pathway is involved in the regulation of angiogenesis because the tumor promoter phorbol myristic acetate (PMA) is a potent inhibitor of FGF-induced endothelial cell proliferation and an inducer of differentiation into capillary-like tubules. Because immediate-early (IE) genes have been shown to be involved in critical regulatory events, we have cloned and characterized PMA-inducible IE genes from human umbilical vein endothelial cells (HUVEC). Collagenase type-I and a novel gene termed edg-1 were isolated as abundant PMA-inducible transcripts. The structure of edg-1 suggests that it encodes a novel G-protein coupled receptor. Furthermore, an isotype of cyclooxygenase (Cox) enzyme, Cox-2, was also induced as an IE gene in HUVEC. The expression of immunoreactive Cox isotypes in vivo correlates with the angiogenesis that occurs in chronic inflammatory diseases such as rheumatoid arthritis (RA). Because prostaglandins induce inflammation and angiogenesis, exaggerated and persistent expression of the Cox-2 may be important in maintaining the inflammatory disease phenotype. Regulated induction of IE genes such as edg-1, collagenase type I and Cox-2 may be important in physiological events that require angiogenesis; however, exaggerated and dysregulated expression of IE genes may result in enhanced angiogenesis, a characteristic of chronic inflammatory diseases and solid tumor growth.