The risk of an anastomotic leakage (AL) following Ivor-Lewis esophagectomy is increased in patients with calcifications of the aorta or a stenosis of the celiac trunc. Ischemic conditioning (ISCON) of the gastric conduit prior to esophagectomy is supposed to improve gastric vascularization at the anastomotic site. The prospective ISCON trial was conducted to proof the safety and feasibility of this strategy with partial gastric devascularization 14 days before esophagectomy in esophageal cancer patients with a compromised vascular status. This work reports the results from a translational project of the ISCON trial aimed to investigate variables of neo-angiogenesis. Twenty esophageal cancer patients scheduled for esophagectomy were included in the ISCON trial. Serum samples (n = 11) were collected for measurement of biomarkers and biopsies (n = 12) of the gastric fundus were taken before and after ISCON of the gastric conduit. Serum samples were analyzed including 62 different cytokines. Vascularization of the gastric mucosa was assessed on paraffin-embedded sections stained against CD34 to detect the degree of microvascular density and vessel size. Between November 2019 and January 2022 patients were included in the ISCON Trial. While serum samples showed no differences regarding cytokine levels before and after ISCON biopsies of the gastric mucosa demonstrated a significant increase in microvascular density after ISCON as compared to the corresponding gastric sample before the intervention. The data prove that ISCON of the gastric conduit as esophageal substitute induces significant neo-angiogenesis in the gastric fundus which is considered as surrogate of an improved vascularization at the anastomotic site.