Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues
- Department of Pathology, University of Southern California, Los Angeles (United States)
- Centro Interdisciplinar de Investigacao em Sanidade Animal (CIISA), Lisbon Technical University, Lisbon (Portugal)
- Department of Vascular Surgery, 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang (China)
- Department of Surgery, University of Southern California, Los Angeles (United States)
- Vasgene Therapeutics, Los Angeles, CA (United States)
Highlights: Black-Right-Pointing-Pointer Low dose Dll4-Fc increases vascular proliferation and overall perfusion. Black-Right-Pointing-Pointer Low dose Dll4-Fc helps vascular injury recovery in hindlimb ischemia model. Black-Right-Pointing-Pointer Low dose Dll4-Fc helps vascular injury recovery in skin flap model. Black-Right-Pointing-Pointer Dll4 heterozygous deletion promotes vascular injury recovery. Black-Right-Pointing-Pointer Dll4 overexpression delays vascular injury recovery. -- Abstract: Notch pathway regulates vessel development and maturation. Dll4, a high-affinity ligand for Notch, is expressed predominantly in the arterial endothelium and is induced by hypoxia among other factors. Inhibition of Dll4 has paradoxical effects of reducing the maturation and perfusion in newly forming vessels while increasing the density of vessels. We hypothesized that partial and/or intermittent inhibition of Dll4 may lead to increased vascular response and still allow vascular maturation to occur. Thus tissue perfusion can be restored rapidly, allowing quicker recovery from ischemia or tissue injury. Our studies in two different models (hindlimb ischemia and skin flap) show that inhibition of Dll4 at low dose allows faster recovery from vascular and tissue injury. This opens a new possibility for Dll4 blockade's therapeutic application in promoting recovery from vascular injury and restoring blood supply to ischemic tissues.
- OSTI ID:
- 22207687
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 418, Issue 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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