Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues

Highlights: ► Low dose Dll4-Fc increases vascular proliferation and overall perfusion. ► Low dose Dll4-Fc helps vascular injury recovery in hindlimb ischemia model. ► Low dose Dll4-Fc helps vascular injury recovery in skin flap model. ► Dll4 heterozygous deletion promotes vascular injury recovery. ► 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.