We are interested in the molecular controls that govern blood vessel formation during mouse development. The vasculature is one of the first organ systems to form and function during embryonic development, and it changes as extensively as development proceeds to meet the changing needs of the fetus. Many molecular processes used during embryonic blood vessel formation are reused when blood vessels are formed inappropriately by a solid tumor, and tumor angiogenesis is one important factor in the growth and spread of cancer and one that is increasingly a target of new cancer therapies. We use a model in which mouse embryonic stem cells differentiate in the incubator to form several cell types, including blood vessels. We studied embryonic stem cells with a targeted mutation in a gene required for blood vessel formation in the embryo, and we showed that lack of this gene prevents differentiation of blood vessels as stem cells differentiate. Moreover, the mutant cultures accumulate cells that express different markers from mature endothelial cells, and we hypothesize that these are precursor cells that are prevented from maturing by the mutation. We will study these cells to better understand how endothelial cells are formed and how they are incorporated into blood vessels. We will learn more precisely where the block in development occurs in the absence of specific genes using this approach. We have initiated in vivo studies to complement our culture assays.

We are also interested in how blood vessels interact with hematopoietic cells. Macrophages are blood cells that help with the immune response in the adult. Macrophages also form during development before the need for an immune system. They have phagocytic properties, which means they can "eat" dead cells. Because they are associated with areas of change in the embryo, they are thought to help with tissue remodeling - for example, they congregate between the digits of the developing hand where the tissue is being degraded. We are interested in how macrophages move from the blood vessels where they are made to areas of remodeling. We recently showed that macrophages form in the blood vessels made from mouse embryonic stem cells that differentiate in vitro, and they migrate out from the vessels. We are currently studying embryonic stem cells with mutations in macrophage development to better understand their development and function.