The B3 subfamily of integrins are two-way signaling receptors that play essential roles in cell biology. Their influences on platelet function and vascular biology are particularly prominent. aVB3 receptor serves as a crucial regulation of angiogenesis, the process of blood vessel growth in adult organism which underlies a number of pathologies, including ischemic injury, cancer and tissue repair. Recent studies demonstrated that angiogenesis is a systemic process where vascular cells coordinate actions with immune cells of blood and tissue origin, and circulating blood components. Using a variety of in vivo models we have shown that activation of aVB3 occurs on endothelium at the sites of active angiogenesis and appears to control several angiogenesis-dependent responses including recovery after ischemia, tumor growth and wound healing. Using a knockin mouse model expressing mutant form of B3 unable to undergo phosphorylation, we demonstrated that B3 phosphorylation is essential for neovascularization in vivo. However, abnormal angiogenesis in B3 knockin mice was completely reversed by bone marrow transplantation was and appear to be dictated primarily by B3 integrin on bone marrow derived (BMDC) cells. Many of these recruited cells express CXCR4, a receptor for SDF-1. Moreover, SDF-1 treatment of BMDC seems to modulate cell adhesion via (33 integrin. These studies identified a novel and unconventional function of B3 integrin in angiogenesis and emphasizes that the process of angiogenesis involve co-operation of numerous cell types and tissues. The overall hypothesis to be tested is that aVB3 activation and phosphorylation are essential for in vivo cooperation between blood, bone marrow-derived and endothelial cells. The following Specific Aims are proposed to test our hypothesis:
Aim I. To assess the role of p3 integrin activation and phosphorylation on the interactions between endothelial, bone marrow derived cells and platelets during angiogenesis in vivo. Double transgenic lines, DiYF-GFP and p3-/- GFP mice will be utilized for visualization of BMDC in bone marrow chimeras. We will also determine the role of platelet B3 on angiogenesis and recruitment of BMDC.
Aim II. To assess the molecular and cellular mechanisms controlling interaction between circulating blood cells and endothelium and determine the role of p3 integrin in this process. Endothelial and BMDC cells from WT, B3-/- and B3 knockin mice as well as cells characterized by impaired integrin activation (from Project 1 and 2) will be used.
Aim III. To assess the role of integrin activation in the process of p3 integrindependent adhesion of BMDC to endothelium. We will determine the role of SDF-1/CXCR4 axis in integrinmediated responses. These studies will delineate the cellular and molecular mechanisms of angiogenesis and result in identification of novel therapeutic strategies to treat ischemia, wound and other pathologies.
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