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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-M (02))
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Schramm, Charlene A
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Weill Medical College of Cornell University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Lacko, Lauretta A; Hurtado, Romulo; Hinds, Samantha et al. (2017) Altered feto-placental vascularization, feto-placental malperfusion and fetal growth restriction in mice with Egfl7 loss of function. Development 144:2469-2479
Kao, Der-I; Lacko, Lauretta A; Ding, Bi-Sen et al. (2015) Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling. Stem Cell Reports 4:181-9
Massimiani, M; Vecchione, L; Piccirilli, D et al. (2015) Epidermal growth factor-like domain 7 promotes migration and invasion of human trophoblast cells through activation of MAPK, PI3K and NOTCH signaling pathways. Mol Hum Reprod 21:435-51
Lacko, Lauretta A; Massimiani, Micol; Sones, Jenny L et al. (2014) Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia. Mech Dev 133:163-76
Bambino, Kathryn; Lacko, Lauretta A; Hajjar, Katherine A et al. (2014) Epidermal growth factor-like domain 7 is a marker of the endothelial lineage and active angiogenesis. Genesis 52:657-70
Nichol, Donna; Stuhlmann, Heidi (2012) EGFL7: a unique angiogenic signaling factor in vascular development and disease. Blood 119:1345-52
Li, Jia; Stuhlmann, Heidi (2012) In vitro imaging of angiogenesis using embryonic stem cell-derived endothelial cells. Stem Cells Dev 21:331-42
Nichol, Donna; Shawber, Carrie; Fitch, Michael J et al. (2010) Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7. Blood 116:6133-43
Durrans, Anna; Stuhlmann, Heidi (2010) A role for Egfl7 during endothelial organization in the embryoid body model system. J Angiogenes Res 2:4
Campagnolo, Luisa; Moscatelli, Ilana; Pellegrini, Manuela et al. (2008) Expression of EGFL7 in primordial germ cells and in adult ovaries and testes. Gene Expr Patterns 8:389-96