A Nuclear Receptor COUP-TFII in Vascular Function: Angiogenesis and Tumoirgenesis

DESCRIPTION (provided by applicant): COUP-TFII is a member of the nuclear receptor superfamily that plays a critical role in organogenesis during embryonic development. In the last funding period, we demonstrated that COUP-TFII is essential for vein specification and lymphatic vessel formation. Loss of COUP- TFII in vein endothelial cells renders the vein to behave like an artery, while mis-expression of COUP-TFII in the artery converts the artery to be vein-like. These results establish COUP-TFII as the first transcription factor essential for vein specification. We also demonstrated that primitive lymphatic sacs fail to form in mice lacking endothelial COUP-TFII, thus supporting the century-old hypothesis that lymphatic endothelial cells are derived from vein endothelial cells. COUP-TFII is expressed in the vein and lymphatic endothelial cells not only during embryonic development but also in the adult. However, whether COUP-TFII is necessary for the functional maintenance of these vessels and whether COUP-TFII plays a role in the pathogenesis of diseases caused by dysfunction of such circulatory networks, remain to be determined. To address how COUP-TFII specifies and maintains vessel function, we will identify the direct downstream targets that mediate COUP-TFII function and uncover the signaling pathways that are impacted by COUP-TFII. In addition, while our previous work showed that COUP-TFII is important for angiogenesis in embryos, we now show that COUP-TFII is also important for angiogenesis in the adult. Since angiogenesis is critical for sustaining tumor growth and metastasis, the major cause of mortality in cancer, it is crucial to assess the role of COUP-TFII in tumor growth and dissect its molecular mechanisms in controlling angiogenesis. Based on our findings, we hypothesize that COUP-TFII plays critical roles in vessel function during embryonic development and in the adult. To elucidate how COUP-TFII controls vein and lymphatic function as well as angiogenesis and tumorigenesis, two specific aims are proposed: Aim 1. Investigate the role of COUP-TFII in vessel development and target gene regulation. We will determine whether COUP-TFII is essential for the maintenance of vein and lymphatic vessel function, and identify COUP-TFII downstream targets that mediate COUP-TFII action to control vein and lymphatic vessel function. Aim 2. Investigate the role of COUP-TFII in angiogenesis and tumorigenesis. We will determine how COUP-TFII regulates angiogenesis and tumor growth in adult mice as well as analyze the function of COUP-TFII in cell growth and tumorigenesis in an ex vivo model. Finally, we will determine the role of COUP-TFII, both loss of function and gain of function, in tumorigenesis. PUBLIC HEALTH RELEVANCE: Blood and lymphatic vessels constitute major circulatory networks, and dysfunctions in these networks often result in diseases and cancers. Here, we propose to study how a nuclear receptor, COUP-TFII, regulates the functions of vascular networks in the context of angiogenesis and tumorigenesis. Since the activity of the COUP-TFII receptor could be controlled by ligands, our studies could lead to discoveries of new therapeutic agents for potential vascular disease intervention.

DESCRIPTION (provided by applicant): COUP-TFII is a member of the nuclear receptor superfamily that plays a critical role in organogenesis during embryonic development. In the last funding period, we demonstrated that COUP-TFII is essential for vein specification and lymphatic vessel formation. Loss of COUP- TFII in vein endothelial cells renders the vein to behave like an artery, while mis-expression of COUP-TFII in the artery converts the artery to be vein-like. These results establish COUP-TFII as the first transcription factor essential for vein specification. We also demonstrated that primitive lymphatic sacs fail to form in mice lacking endothelial COUP-TFII, thus supporting the century-old hypothesis that lymphatic endothelial cells are derived from vein endothelial cells. COUP-TFII is expressed in the vein and lymphatic endothelial cells not only during embryonic development but also in the adult. However, whether COUP-TFII is necessary for the functional maintenance of these vessels and whether COUP-TFII plays a role in the pathogenesis of diseases caused by dysfunction of such circulatory networks, remain to be determined. To address how COUP-TFII specifies and maintains vessel function, we will identify the direct downstream targets that mediate COUP-TFII function and uncover the signaling pathways that are impacted by COUP-TFII. In addition, while our previous work showed that COUP-TFII is important for angiogenesis in embryos, we now show that COUP-TFII is also important for angiogenesis in the adult. Since angiogenesis is critical for sustaining tumor growth and metastasis, the major cause of mortality in cancer, it is crucial to assess the role of COUP-TFII in tumor growth and dissect its molecular mechanisms in controlling angiogenesis. Based on our findings, we hypothesize that COUP-TFII plays critical roles in vessel function during embryonic development and in the adult. To elucidate how COUP-TFII controls vein and lymphatic function as well as angiogenesis and tumorigenesis, two specific aims are proposed: Aim 1. Investigate the role of COUP-TFII in vessel development and target gene regulation. We will determine whether COUP-TFII is essential for the maintenance of vein and lymphatic vessel function, and identify COUP-TFII downstream targets that mediate COUP-TFII action to control vein and lymphatic vessel function. Aim 2. Investigate the role of COUP-TFII in angiogenesis and tumorigenesis. We will determine how COUP-TFII regulates angiogenesis and tumor growth in adult mice as well as analyze the function of COUP-TFII in cell growth and tumorigenesis in an ex vivo model. Finally, we will determine the role of COUP-TFII, both loss of function and gain of function, in tumorigenesis. PUBLIC HEALTH RELEVANCE: Blood and lymphatic vessels constitute major circulatory networks, and dysfunctions in these networks often result in diseases and cancers. Here, we propose to study how a nuclear receptor, COUP-TFII, regulates the functions of vascular networks in the context of angiogenesis and tumorigenesis. Since the activity of the COUP-TFII receptor could be controlled by ligands, our studies could lead to discoveries of new therapeutic agents for potential vascular disease intervention.