Angiogenesis is crucial for the development of a functional circulatory system in the vertebrate embryo. Central to these processes are the endothelial cells (EC) that form a continuous layer lining the blood vessels and constitute a dynamic system that changes in response to environmental stimuli. Epidermal growth factor-like 7 (EGFL7) is expressed by EC and is present both in soluble of ECM-bound forms and may act both in an autocrine and paracrine manner. Expression in adult endothelium is low but becomes induced during physiological and pathological angiogenesis. We have previously shown that Egfl7 is a critical, pro-angiogenic regulator of angiogenesis during embryonic development and in during post-natal angiogenesis in the retina. The mechanisms by which Egfl7 signals are transduced are not well understood. However, our studies show in vivo, that EGFL7 interacts with endothelial Notch and modulates Notch intracellular signaling. Little is known about its role in response to microvascular injury and repair. The bone marrow (BM) vasculature is an ideal model to address these questions because injury and regeneration of the sinusoidal endothelium and the HSPC residing in the vascular niche can be studied in a well-defined setting. Importantly, this model is relevant for pathological angiogenesis i.e. during tissue damage, ischemia, and tumor angiogenesis. A central hypothesis of this proposal is that EGFL7 acts in response to injury of the BM vasculature to promote endothelial and hematopoietic regeneration that restores the damaged tissue. We further propose that EGFL7 acts through an autocrine mechanism to promote neoangiogenesis in response to vascular injury via cross-talk with VEGF and Notch, and that EGFL7 acts through a paracrine mechanism as an angiocrine factor secreted by sinusoidal EC in the BM vascular niche to promote hematopoiesis. We will test these hypotheses in three specific aims. First, we will determine the role of Egfl7 in the BM vascular niche. Second, we will investigate the molecular and biochemical basis of Egfl7 signaling in primary human EC. Third, we will identify mechanisms of EGFL7 signaling in the BM vascular niche. Endothelial cells constitute a dynamic system that changes in response to environmental stimuli, including injury of the microvasculature. Understanding how these processes are orchestrated in a living organism may lead to treatments in which endothelial cells aid the repair of damaged vessels or restrict the blood supply of tumors.
The project will investigate the role of epidermal growth factor-like protein 7 (EGFL7) in angiogenesis and vascular injury. EGFL7 is a protein that is expressed by endothelial cells of blood vessels and is present both in a soluble form and bound to the extracellular matrix. This proposal will investigate how EGFL7 supports growth and maintenance of the proper architecture of specialized blood vessels and blood cells in the bone marrow. We will also determine how EGFL7 facilitates the regenerating of functional bone marrow blood vessels and blood cells after injury by myelosuppressive treatment with chemicals and irradiation. We anticipate that the protein may proof useful in the clinic to aid in recovery from chemotherapy, heart attack and ischemia and may provide a means to inhibit the growth of solid tumors.
