(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Adult hematopoietic stem cells (HSCs) are known to rely on signals from neighboring microenvironmental cells, such as the endothelial populations. While the role of blood vessels in promoting metastatic progression of solid tumors has been extensively studied, their function in the initiation and progression of early myeloid disorders, such as myelodysplastic syndromes (MDS), is less defined. MDS is characterized by a block in HSC differentiation and progressive bone marrow failure, especially in the elderly. With our ageing population, >10,000 new cases are diagnosed in the US every year. Since many patients with MDS develop aggressive therapy-resistant acute myeloid leukemias (AML), there is a significant need to understand mechanisms promoting MDS progression. Extensive work has shown increased angiogenesis in MDS patient bone marrow biopsies, possibly induced by angiogenic factors secreted by MDS cells. Higher disease burden often correlates with increasing microvascular density. Endothelial niche-driven signals are known to be critical for survival and chemoresistance of AML. These observations indicate a functional role for aberrant angiogenesis in promoting disease progression. However, it is not known when the endothelial niche remodeling initiates during MDS progression, what are the molecular changes that occur within the endothelial cells over time, and if the newly formed blood vessels provide support for disease progression. Based on the extensive remodeling of the endothelial niche in MDS, and the requirement for endothelial niche-driven signals in AML that can develop from MDS, we hypothesize that the altered vascular bone marrow niche provides support for MDS initiation as well as growth and progression of MDS. To test this, we will determine the spatiotemporal changes in the bone marrow endothelial niche and determine the functional role of the altered endothelial cells on MDS progression. In the long term, our work may help in designing novel therapeutic approaches aimed at inhibiting endothelial cell remodeling in MDS.