Increased Plasma VEGF Levels in Patients with Cerebral Large Artery Disease Are Associated with Cerebral Microbleeds

BACKGROUND/PURPOSE: Because atherosclerotic factors and antithrombotic agents sometimes induce cerebral microbleeds (CMBs), patients with cerebral large artery disease (CLAD) tend to have more CMBs than control subjects. On the other hand, VEGF contributes to the disruption of the blood-brain barrier, and it may induce parenchymal edema and bleeding. We conducted a study to evaluate the role of vascular endothelial growth factor (VEGF) in the occurrence of CMBs in patients with CLAD. METHODS: CLAD is defined as stenosis or occlusion of either the carotid artery or the middle cerebral artery of 50% or more. We prospectively registered patients with CLAD who were hospitalized in our neurocenter. Biological backgrounds, atherosclerotic risk factors, administration of antithrombotics before hospitalization, and levels of cytokines and chemokines were evaluated. Susceptibility-weighted imaging or T2*-weighted MR angiography was used to evaluate CMBs. The Brain Observer MicroBleed Scale (BOMBS) was used for CMB assessments. Images were analyzed with regard to the presence or absence of CMBs. We also examined plasma VEGF concentrations using a commercial ELISA kit. Because more than half showed plasma VEGF levels below assay detection limits (3.2 pg/mL), the patients were dichotomized by plasma VEGF levels into two groups (above and below the detection limit). After univariate analyses, logistic regression analysis was conducted to determine the factors associated with the CMBs after adjustment for age, sex, the presence of hypertension, and administration of antithrombotic agents. A similar analysis with CMBs separated by location (cortex, subcortex, or posterior circulation) was also conducted. RESULTS: Sixty-six patients (71.1 ± 8.9 years, 53 males and 13 females) were included in this study. Plasma VEGF levels were not correlated with age, sex, and atherosclerotic risk factors; however, patients with VEGF levels >3.2 pg/mL tended toward more frequent CMBs (60.0 vs. 32.6%, in the presence and absence of CMBs, p = 0.056). With regard to the location of CMBs, those in the cortex and/or at the gray-white junction were observed more frequently in the patients with VEGF levels >3.2 pg/mL after multivariable analyses (odds ratio: 3.80; 95% confidence interval: 1.07–13.5; p = 0.039). CONCLUSIONS: In patients with CLAD, elevated plasma VEGF might be associated with CMBs, especially those located in the cortex and/or at the gray-white junction.