HYPOXIA REGULATION OF VEGF/VEGF RECEPTORS IN KELOIDS

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We postulate that an imbalance in vascular homeostasis could contribute to a hypervascular state at the inflammatory border (erythematous) or a hypovascular state at the stable portion (classical keloid) of the keloid lesion, as observed clinically and histologically. The hypovascular or hypoxic state present at the stable portion is the key factor for induction and prolongation of the hypervascular and hyperpermeable features. These features, characteristic of the granulation tissue phenotype, are responsible for the maintenance of an enriched milieu of cytokines and growth factors for continuing support of dermal growth. Our study will focus on vascular endothelial growth factor (VEGF) as a major regulator of keloid vascular homeostasis. The proposed keloid study model will be established on three clinically distinct lesional sites--inflammatory (erythematous), stable (classical keloid) and central portion (regressing scar)--which represent the pathologic course of keloid formation. The role of transcription factor, hypoxia- inducible factor, HIF-1, and hypoxia-responsive element, HRE, in the regulation of hypoxic-induced VEGF expression at the stable portion of the keloid will be determined in correlation with the granulation tissue phenotype observed at the inflammatory border. The interaction between angiogenic stimuli, VEGF, HIF-1, and the extracellular proteases, urokinase plasminogen activator, uPA, and its inhibitor, PAI-1, will be investigated in our unique three-distinct-sites approach to elucidate the molecular basis of differential vascular formation in keloids. We hypothesize that a dysregulation in wound angiogenesis contributes to a differential distribution of vascular network, hypovascular or hypoxic at the stable portion of the lesion versus hypervascular and hyperpermeable at the inflammatory border, establishing the benign growth of the keloid phenotype. Our hypothesis will be tested using the following specific aims: 1) To confirm that VEGF/VEGF receptor(s) and uPA/PAI-1 are differentially expressed in human microvascular endothelium of keloids at the three distinct sites compared to adjacent clinically normal skin; 2) To study the effect of hypoxic stress on the expression of uPA/PAI-1 and VEGF/VEGF receptor(s), receptor affinity, biological functions including phosphorylation and in vitro angiogenic activity; 3) To study the effect of VEGF on the expression of uPA /PAI-1 and their role in keloid vascular homeostasis; and 4) To delineate the role of transcription factor, HIF-1, and HRE on hypoxia-induced VEGF expression.