Increased Vegfa-165a/Vegfa-165b Ratio In Patients With Moyamoya Compared To Intracranial Atherosclerosis (Icas) And Controls.

Introduction: Recent work in cancer biology has identified splice variants of human VEGF-A that inhibit angiogenesis. These isoforms arise from differential splicing of exon 8: a proangiogenic VEGF-A165a and the antiangiogenic VEGF-A165b. The purpose of this study was to compare circulating VEGF-A165a / VEGF-A165b ratios in patients with ICAS to those of patients with moyamoya and controls with no vascular or tumoral disease. Identifying a potential target to facilitate the generation of spontaneous collaterals could open novel treatment avenues for ICAS patients. Methods: This is a prospective observational study of circulating VEGF-A165a and VEGF-A165b. Serum samples were collected at baseline, 1 week, 1 month, 3 months, and 6 months after enrollment. Levels of VEGFA-165a and VEGFA-165b were determined by a multiplex sandwich ELISA. All samples were run in duplicate with an acceptance threshold for intersample variability of less than 20%. A mixed model regression model was built to predict square root transformed VEGF-A165a / VEGF-A165b ratio using age and etiology as the predictor variables. A repeated autoregressive 1 structure was used to account for repeated measures and subject random effects were used to account for intersubject variability. Results: The study population consisted of 72 individuals with ICAS (age = 61.7±12.0), 8 with moyamoya (age = 42.7±12.6), and 7 controls (age = 44.3±13.9). A total of 230 samples were collected (ICAS: 188, moyamoya: 21, control: 21). One outlier was excluded due to an exorbitantly high VEGFA-165a concentration. VEGFA-165a/VEGFA-165b ratios were as follows for each etiology: ICAS (0.15±0.17), moyamoya (0.38±0.52), and control (0.10±0.12). Mixed model regression analysis found a significant independent positive association of moyamoya to elevated VEGF-A165a/ VEGF-A165b ratio (p=0.03). Conclusion: In this prospective analysis of VEGF-A165a/ VEGF-A165b ratio, moyamoya patients had elevated ratios compared to ICAS and controls. This finding supports the concept that VEGF-A165b could serve as a new pharmacological target to treat cerebral ischemia in patients with ICAS as its neutralization may augment the activities of proangiogenic growth factors in developing collaterals.