Angiogenesis, the formation of new blood vessels from existing blood vessels, is a fundamental biological process that requires not only the action of vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR2) system, but also activation of the wingless (Wnt) pathway. However, the underlying mechanisms of Wnt signaling in angiogenesis are not clear. The goal of the renewal of R01-HL079356 is to examine how lipid phosphate phosphatase-3 (LPP3), previously called phosphatidic acid phosphatase-2b (PAP2b), regulates the angiogenic phenotypes of endothelial cells (ECs). In the previous funding cycle, we characterized how LPP3 promotes b-catenin- mediated transcriptional activation of T-cell factor-4/lymphoid enhancer factor-1 (TCF4/LEF-1) target genes. We showed that phosphatase tensin (PTEN)-dependent LPP3 activation of b-catenin was responsible for the synthesis and deposition of vascular endothelial (VE)-cadherin and fibronectin, which are key regulators of cell-cell and cell-matrix adhesion events. Notably, we have determined that Tie-2Cre- mediated conditional deletion of the Lpp3 gene in ECs induces apoptosis of these cells in 13.5-14.5 embryonic (E) days. Therefore, in this renewal application, we will test the novel hypothesis that LPP3 is required to resist one or more pro-apoptotic signals during angiogenesis.
AIM#1 will outline studies to characterize the mechanisms whereby LPP3 regulates the association of b-catenin with PTEN to promote cell-cycle progression and protect cells from apoptosis. In addition, we will address the hypothesis that the ability of the LPP3/PTEN/b-catenin signaling module to promote cell survival is critical for angiogenesis. We predict that suppression of this survival pathway will promote apoptosis of these cells in tissue microenvironments where the intrinsic apoptotic pathway is otherwise limiting.
AIM#2 will investigate the effect of timed deletion of Lpp3 in ECs involved in lung microvessel remodeling on the sensitivity of airway vasculature to pro-apoptotic stimuli. These observations will reveal how LPP3 influences cell survival in the microenvironments of adult tissue. The studies proposed in this application will establish a molecular basis to support our hypothesis that the angiogenic phenotypes of ECs depend on the ability of these cells to sense the LPP3-mediated b-catenin-dependent cell survival pathway. The results of these investigations may reveal new therapeutic strategies to regulate angiogenesis, and the apoptotic properties of endothelial and tumor cells.
These studies will address the role of Lipid Phosphate Phosphatase-3 (LPP3) in endothelial cell biology as it relates angiogenesis, cardiovascular diseases, and cancer, and to generate molecular targets for diagnosis, prognosis and treatment of diseases associated with pathological angiogenesis.
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