Levels of endogenous adropin determine the susceptibility to ischemic stroke injury in male and female mice with no significant differences in cerebrovascular anatomy among genotypes. A-H, Adult (10–12 weeks) male and female adropin overexpressing (AdrTg), heterozygous adropin-deficient (Enho+/-), homozygous adropin-deficient (Enho−/−) mice and their corresponding wild-type littermates were subjected to pMCAO and euthanized at 48h after cerebral ischemia to measure infarct volume by TTC staining. A, B, Representative images of TTC-stained brain sections and graphical data show that deficiency of Enho gene in male mice resulted in a significant increase in brain infarct volume compared to Enho+/+ controls. One-way ANOVA with Bonferroni post-tests, **P < 0.01, n = 13–17 per group. Conversely, transgenic overexpression of adropin (AdrTg) in male mice resulted in a smaller coronal brain infarction after 48h following pMCAO (C) and total infarct volume (D) compared to WT littermates. Unpaired t-test, **P < 0.01, n = 16–17 per group. Similarly, Enho deficiency in female mice also resulted in a significant increase in brain infarct volume compared to Enho+/+ controls (E, F). In contrast, a smaller brain infarct size was observed in female AdrTg mice at 48h after pMCAO compared to their WT littermates (G, H). Unpaired t-test, *P < 0.05, **P < 0.01, n = 12–17 per group. I–N, Intravascular perfusion with latex blue shows permanent staining of small vessels on the dorsal surface of brains in adult (10–12 weeks) male Enho−/−, AdrTg and their corresponding wild-type littermates. A yellow line connected adjacent anastomosis points, and the distance from the midline to the line of anastomoses was measured at 2, 4, and 6 mm from the frontal pole. Quantification of the distance of the anastomotic points between the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) from the midline showed no differences in the supplying territory of the MCA between Enho−/− and Enho+/+ mice (I–K), as well as the AdrTg and the corresponding WT mice (L–N). Unpaired t-test. Enho+/+ (n = 7), Enho−/− (n = 8), WT (n = 7), AdrTg (n = 7). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)