Very little is known about the role that circulating heparin binding angiogenic growth factors play in the pathogenesis of bleeding disorders induced by heparin-like drugs or heparinoids in critically ill children. We have found a new role for Fibroblast Growth Factor -2 (FGF-2), an angiogenic heparin binding growth factor (HBGF), in the pathogenesis of bleeding disorders induced by heparin and pentosan polysulfate, an heparin-like drug. Others have found that an FGF binding protein (BP-1) that enhances the activity of FGF-2 induces vascular leakage and bleeding in the chicken CAM assay. Based on these findings, we hypothesize that FGF-2, alone or in combination with BP-1 or VEGF-A, enhances the capillary permeability changes induced by heparin-like drugs and increases their risk of causing lethal hemorrhages. This hypothesis will be tested in three specific aims:
Aim 1 will define first the basic signaling pathways by which FGF-2, BP-1, VEGF-A, and plasma urine samples harvested from critically ill children, alone or in combination with heparin, increase the permeability of cultured human microvascular endothelial cells (HMVEC), and determine the relative contribution of the VEGFR-2, Tie-2, Src, and Rho kinase pathways in this process. Second, plasma/urine samples harvested from critically ill children with high plasma levels of FGF-2 treated with or without heparin, will be used to explore similar pathways and develop an HMVEC-permeability bioassay to discover new biomarkers to identify children at risk of bleeding when treated with heparin.
In aim 2 tet-inducible Tg mice will be used to determine the relative contribution of BP-1 in the pathogenesis of these bleeding disorders. In addition, endothelial cells from TVA-Tg mice will be transduced with angiogenic retroviral vectors (RCAS), to enhance the release of FGF-2 and other HBGF into the circulation, and define their role in the pathogenesis of hemorrhages induced by heparinoids.
Aim 3 will test the hypothesis that Angiopoietin-1 (Ang-1), an angiogenic anti-permeability growth factor, and the FGF-2 receptor tyrosine kinase inhibitor PD173074, will improve the clinical outcome of hemorrhages induced by heparinoids and FGF-2 in mice. The relative contribution and role of the Rho kinase pathway in this process will be explored as well. These experiments will generate new knowledge related to the role that HBGF released into the circulation of critically ill children play in the clinical outcome of hemorrhages induced by heparin, and test the novel concept that anti- permeability therapies will improve the clinical outcome of these children.
This proposal will test the hypothesis that heparin binding growth factors released into the circulation of critically ill children play a critical role in the development of vascular leakage and lethal hemorrhages induced by heparin-like drugs. In addition, we will test the novel concept that anti-permeability therapies will improve the clinical outcome of lethal hemorrhages induced by heparin-like drugs in in wild type and transgenic mice. These findings could have wider clinical implications for the treatment of critically ill children subjected to extracorporeal procedures) that required the use of heparin (cardiac bypass, ECMO, and hemodialysis and young children with vascular tumors and other angiogenic diseases.
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