Promoting angiogenesis is both a critical aspect for tissue regeneration and a potential effective therapy for cardiovascular diseases. Inspired by the recent findings that systemic introduction of Notch inhibitors reduced blood flow to tumor tissues by forming excessive yet dysfunctional vasculature, we proposed that precisely controlled partial and local Notch inhibition might enhance regional neovascularization, by altering the responsiveness of local endothelial cells and/or progenitors to angiogenic stimuli. We tested our hypothesis with in vitro assays with human endothelial cells, as well as in a rodent hindlimb ischemia model. In vitro, an optimal level of inhibition of Notch signaling by gamma secretase inhibitor (GSI) significantly increased the proliferation, migration and sprout formation of human endothelial cells (derived from diabetic and non-diabetic subjects) in response to VEGF stimulation. In vivo, delivery of an appropriate combination of GSI and VEGF from an injectable alginate hydrogel system to ischemic hindlimbs led to a greater recovery of blood flow than VEGF or GSI alone; perfusion levels reached 80% of the normal level by week 4 with combined GSI and VEGF delivery. Strikingly, direct intramuscular or intraperitoneal injection of GSI did not result in the same level of improvement, suggesting that the extended presence of GSI (gel delivery) is important for its activity. Potential side effects of GSI delivery were also investigated by examining the differentiation of crypt cells in the small intestine. The optimal dose of GSI delivered from alginate hydrogels did not show any adverse effects, in contrast to systemic introduction of GSI. Altogether, these results suggested a new approach to promote angiogenesis by fine-tuning Notch signaling, and may provide new options to treat patients with diseases, such as diabetes, that can diminish angiogenic responsiveness.