The physiologic event which lead to local vaso-occlusion in sickle cell disease are complex. It is clear that a number o processes are involved, including local hypoxia, vasoconstriction, and adhesion of sickled cells to the vascular endothelium, but the molecular mechanisms underlying these events have not been previously elucidated. A recent study suggest mechanisms mediated by the vascular stasis. This vasoconstriction, in combination with the tissue hypoxia, may contribute in a major way to local sickling events. Hypoxia initiates the activation of specific genes in human vascular endothelial cells resulting in the elaboration of potent protein products able to induce vasoconstriction, smooth muscle hyperplasia, and cell adhesion. PDGF, for example, is not only a potent vasoconstrictor, but is also a powerful growth factor for vascular smooth muscle. Chronic production of PDGF by endothelium in hypoxic pulmonary vascular beds could stimulate the smooth muscle hyperplasia and fibrosis found in sickle cell chronic lung disease. An increased tendency of sickled erythrocytes and leukocytes to adhere to vascular endothelial cells has been well documented and may contribute to the vaso-occlusive events in sickle cell disease. Hypoxia causes the local production of sickled RBC and leukocytes. It is hypothesized that these local vascular responses to hypoxia contribute to the pathology of both the acute and the chronic processes of sickle cell disease.
The Specific Aims of this proposal are: 1) Determine the molecular level at which oxygen tension regulates PDGF and endothelin production; 2) Define the second messenger systems used by the hypoxic sensor; 3) Map the regulatory regions of the PDGF and endothelin genes responsive to oxygen tension; 4) Characterize and isolate the endothelial oxygen-sensor; 5) Determine if other known vasoconstrictors are induced or relaxing factors repressed by hypoxia; 7) Characterize adhesion and chemoattractant molecule synthesis and secretion in response to hypoxia; and 8) Establish whether transcripts of vasoconstrictors and adhesion molecules are increased in endothelium from hypoxic lung or other tissues via in situ hybridization. The long-term expectation is that an understanding of the basic molecular mechanisms responsible for control of vascular tone will lead to new therapies for the maladaptive vascular responses to hypoxia seen in sickle cell anemia.
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