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Endothelial Mutagenesis Uncovers Key Regulatory Pathways that Maintain Vascular Homeostasis


The purpose of the vascular system is to distribute oxygen rich blood to all organs and extremities, to mediate the transport of nutrients and waste, and to deliver immune cells to sites of infection. It is comprised of the heart and a complex, hierarchically branched network of blood vessels through which the blood is pumped. The principal cell type of the blood vessel is the endothelial cell (EC). They are a subclass of epithelial cells that line the blood vessels and like ceramic tiles, provide a flat-slippery surface for the blood to flow past. Healthy blood circulation is critical for organs to be well oxygenated with the transport of red blood cell and free of infection through the delivery of white blood cells.

Under normal physiological conditions, adult EC are quiescent and do not proliferate. However, in pathological conditions like wound healing and cancer, secreted growth factors and inflammatory cytokines induce endothelial cells to turn on an angiogenesis program. On the other hand, transformed ECs can be the primary cell type of pathology. One such endothelial cell pathology is vascular anomalies (VAs). The emergence of these lesions requires endothelial cells to accumulate mutations causing them to form malformed vessels or solid tumors. It has been predicted that half of the mutations underlying vascular malformations are unknown, especially those that are non-hereditary and triggered by sporadic, somatic mutations. What is known has been determined through genetic linkage analysis of familial forms of the disease. Here we present the novel results of an in vivo forward genetic screen in murine endothelial cells that modeled vascular anomalies. The majority of the approximately 100 disrupted genes identified have not been previously associated with vascular anomalies. Furthermore, we validated a tumor suppressor (Fndc3b) and an oncogene (Pdgfrb) and demonstrated their causation in endothelial dysfunction. The major significant finding of this study is that endothelial cell homeostasis is heavily governed by regulation of the actin cytoskeleton, cytokine and growth factor signaling, and Hippo signaling pathways.

Also a result of the screen was the revelation that a pathological relationship exists between hemogenic endothelial cells and leukemia. Using the same forward genetic approach in a mouse model, we were able to induced mutagenesis at E9.5 in endothelial cells one day before they turned on their hemogenic program at E10.5. Not only were hematopoietic malignancies generated (both myeloid and lymphoid), but novel mutations associated with these cancers were identified. Here we also present data demonstrating the novel role of Pi4ka (identified in association with myeloid leukemia) in hematopoiesis. Together this work takes a look at the critical role of endothelial cells from three different perspectives (tumor angiogenesis, vascular anomalies, and hemogenic endothelial contribution to leukemia), highlighting their importance in physiology and pathology.

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