Vascular Endothelial Growth Factor (VEGF) is an angiogenic factor that promotes vascular development and preservation; VEGF binds to angiopoietin receptor Tie2 to regulate angiogenesis. VEGF dysregulation is associated with poorer hemodynamic function and increased risk of vascular brain injury. However, little is known about how it is associated with brain volumetric measurements, particularly in young and middle aged adults. In the present study, we investigated associations between circulating VEGF and Tie2 concentrations and brain MRI markers of small vessel disease and atrophy in young and middle-aged adults. Participants in the third generation of the Framingham Heart Study without stroke, large cerebral brain infarcts, and other neurological disorders, who had brain MRI and serum VEGF and Tie2 measurements were included (n=1877, age 46±8, 54% women). Mean interval between blood draw and MRI was 1.5±0.77 years. MRI volumetric measurements of gray (GM) and white matter, white matter hyperintensity (WMH), and cerebrospinal fluid were regressed onto total intracranial volumes to account for differences in head sizes, and the residuals of each regression were used as outcomes in separate models. VEGF and Tie2 were log-transformed to normalize the distributions and were analyzed in SDU as predictors. All analyses were adjusted for age, age2, sex, time between blood draw and MRI, waist-to-hip ratio, systolic blood pressure, hypertension treatment, diabetes mellitus, current smoking, and prevalent cardiovascular disease. Higher circulating VEGF levels were associated with lower hippocampal volume (Estimate by standard deviation units ± se= -0.07±0.03, p=0.041). Higher Tie2 levels were associated with lower total brain (-0.07±0.02, p=0.001) and cortical GM (-0.06±0.02, p=0.008) volumes, and with higher WMH volume (0.04±0.01, p=0.001). Our results suggest that increased levels of VEGF and Tie2 are associated with early gray matter loss and white matter disease in young and middle-aged adults, independent of the effects of vascular risk factors and cardiovascular disease. These preliminary findings suggest a role of growth factors in early brain changes that are observed in small vessel disease and Alzheimer's disease. We plan to expand these findings by relating vascular growth factors to cognitive function, and with Mendelian randomization analyses.