The vascular tree is lined by a quiescent, non-thrombogenic monolayer of endothelial cells which function as a metabolic interface between blood and tissue. Biological events which damage the vessel wall, signal the endothelial cell to migrate, proliferate and differentiate at the site of injury. These events, termed angiogenesis, are crucial for the maintenance of the structural integrity of the vascular tree and are also proposed to significantly contribute to the pathophysiology of human disease in the most general sense. Thus the characterization of factors responsible for regulation of endothelial cell migration, proliferation and differentiation are of paramount importance to Pathology and Medicine. The human endothelial cell (hEC) in vitro, under conditions that minimize proliferation, enters a reversible and ordered pathway of non-terminal differentiation that results in the formation of viable, three dimensional, and tubular microvascular-like structure. During the tenure of this award, this laboratory has demonstrated that (i) cytokines induce hEC quiescence and modulate prominent stable and reversible hEC phenotypic changes in vitro, (ii) cytokines are responsible for the induction of the immediate-early events of the hEC differentiation pathways, (iii) the cytokines-induced immediate-early phenotype includes the reduction of functional growth factor receptors on the hEC surface, (iv) in vivo models for angiogenesis can be established and used to access information relative to the contribution of the non-proliferative aspects of angiogenesis, (v) new and sensitive cDNA cloning techniques can be established and used to describe a set of know and unknown immediate-early hEC differentiation-induced response genes and (vi) human cyclooxygenase (cox) is an immediate-early gene induced by interleukin 1 alpha in hEC. Thus, the goal of this competitive renewal application remains to elucidate the biochemical mechanisms responsible for the modulation of hEC differentiation in vitro and we propose to expand these observations in two directions: (1) to continue to characterize hEC immediate-early differentiation-induced cDNAs and study their expression and possible function during the non-proliferative pathway of hEC non-terminal differentiation in vitro and angiogenesis (both normal and pathological) in vivo and (ii) to utilize the methods that evolved as a result of this application to isolate and characterize late hEC non-terminal differentiation-induced cDNAs. It is anticipated that this effort will provide a more lucid understanding of the biology of the endothelium and the contribution on the non-proliferative aspects of hEC differentiation to the phenomena of angiogenesis in vivo in situations that include would repair, atherogenesis, arthritis, solid tumor growth and vascular disease, in general.
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