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.
|Oh, Myung-Jin; Zhang, Chongxu; LeMaster, Elizabeth et al. (2016) Oxidized LDL signals through Rho-GTPase to induce endothelial cell stiffening and promote capillary formation. J Lipid Res 57:791-808|
|Chatterjee, Ishita; Li, Fei; Kohler, Erin E et al. (2016) Induced Pluripotent Stem (iPS) Cell Culture Methods and Induction of Differentiation into Endothelial Cells. Methods Mol Biol 1357:311-27|
|Wu, Liangtang; Wary, Kishore K; Revskoy, Sergei et al. (2015) Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. Stem Cell Reports 5:10-21|
|Gong, Haixia; Rehman, Jalees; Tang, Haiyang et al. (2015) Corrigendum. HIF2Î± signaling inhibits adherens junctional disruption in acute lung injury. J Clin Invest 125:1364|
|Toya, Sophie P; Wary, Kishore K; Mittal, Manish et al. (2015) Integrin Î±6Î²1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells 33:1719-29|
|Kohler, Erin E; Baruah, Jugajyoti; Urao, Norifumi et al. (2014) Low-dose 6-bromoindirubin-3'-oxime induces partial dedifferentiation of endothelial cells to promote increased neovascularization. Stem Cells 32:1538-52|
|Yamada, Kaori H; Nakajima, Yuki; Geyer, Melissa et al. (2014) KIF13B regulates angiogenesis through Golgi to plasma membrane trafficking of VEGFR2. J Cell Sci 127:4518-30|
|Usatyuk, Peter V; Fu, Panfeng; Mohan, Vijay et al. (2014) Role of c-Met/phosphatidylinositol 3-kinase (PI3k)/Akt signaling in hepatocyte growth factor (HGF)-mediated lamellipodia formation, reactive oxygen species (ROS) generation, and motility of lung endothelial cells. J Biol Chem 289:13476-91|
|Traphagen, Samantha B; Titushkin, Igor; Sun, Shan et al. (2013) Endothelial invasive response in a co-culture model with physically-induced osteodifferentiation. J Tissue Eng Regen Med 7:621-30|
|Kohler, Erin E; Wary, Kishore K; Li, Fei et al. (2013) Flk1+ and VE-cadherin+ endothelial cells derived from iPSCs recapitulates vascular development during differentiation and display similar angiogenic potential as ESC-derived cells. PLoS One 8:e85549|
Showing the most recent 10 out of 17 publications