Angiogenesis, the formation of new blood vessels, is essential for growth and repair, and an irregularity of angiogenesis contributes to numerous malignant, inflammatory and ischemic disorders. Transcription factors that regulate angiogenic gene expression are critical for proper vascular development and homeostasis. Increasing evidence suggests that the combinatorial regulation of endothelial cell transcription plays a crucial role in vascular network formation and maintenance of vascular integrity. Our major goal is to elucidate the transcriptional governance associated with angiogenesis, specifically the interplay of the transcription factors responsible for correct endothelial cell differentiation, sprouting and vascular remodeling. The transcription factor Yin Yang 1 (YY1) is a ubiquitously expressed GLI-Krppel zinc finger-containing transcription factor and contributes to various normal biological processes, including development, differentiation, and cellular proliferation. However, the biological role of YY1 in cardiovascular system remains poorly understood. Our preliminary studies show that endothelial cell-specific knockout of YY1 in mice leads to the mid-gestational embryonic lethality associated with defects of vascular development and angiogenesis. Gene profile analysis of YY1 deficient endothelial cells and yolk sac recognized a number of altered genes, of particular interest was Notch signaling-dependent genes. Increasing evidence supports that the fine-tuning of the Notch signaling pathway governs the proper development of the vascular system. Thus, we hypothesize that YY1 regulates endothelial cell specification, function and angiogenesis through modulating Notch-dependent gene transcription. A combination of molecular, cellular and mouse models will be employed to establish the influence of YY1 on gene expression, endothelial function and angiogenesis. As such, we propose: 1) to determine the molecular mechanisms by which YY1 regulates Notch-dependent angiogenesis-associated genes; 2) to define the biological role and molecular mechanisms of endothelial YY1 in regulation of endothelial cell specification and sprouting angiogenesis; 3) to delineate the physiological role and molecular mechanisms of endothelial YY1 in regulation of ischemic angiogenesis in adults. The information gleaned from these studies is critical to determine how manipulations of transcription factors such as YY1 are critica for designing novel and effective therapies for angiogenesis-related diseases.
Abnormal blood vessel formation either excessively or insufficiently is implicated in many development defects and a large number of diseases, including ischemic heart and limb diseases, cancer, diabetic blindness, age-related macular degeneration and rheumatoid arthritis. This project is designed to elucidate the role of a transcriptional factor called YY1 in regulation of vascular formation and angiogenesis in both normal physiological and pathological conditions. The findings from this project will provide a better understanding of molecular mechanisms underlying blood vessel formation, and will provide an underpinning for the advancement of more efficiently targeted interventions aimed at angiogenesis-dependent diseases.
