Role of Matrix Metalloproteinase-2, Matrix Metalloproteinase-9, and Vascular Endothelial Growth Factor in the Development of Chronic Subdural Hematoma

Abstract

Chronic subdural hematoma (CSDH) is an inflammatory and angiogenic disease. Vascular endothelial growth factor (VEGF) has an important effect on the pathological progression of CSDH. The matrix metalloproteinases (MMPs) and VEGF also play a significant role in pathological angiogenesis. Our research was to investigate the level of MMPs and VEGF in serum and hematoma fluid. Magnetic Resonance Imaging (MRI) shows the characteristics of different stages of CSDH. We also analyzed the relationship between the level of VEGF in subdural hematoma fluid and the appearances of the patients' MRI. We performed a study comparing serum and hematoma fluid in 37 consecutive patients with primary CSDHs using enzyme-linked immunosorbent assay (ELISA). MMP-2 and MMP-9 activity was assayed by the gelatin zymography method. The patients were divided into five groups according to the appearance of the hematomas on MRI: group 1 (T1-weighted low, T2-weighted low, n=4), group 2 (T1-weighted high, T2-weighted low, n=11), group 3 (T1-weighted mixed, T2-weighted mixed, n=9), group 4 (T1-weighted high, T2-weighted high, n=5), and group 5 (T1-weighted low, T2-weighted high, n=8). Neurological status was assessed by Markwalder score on admission and at follow-up. The mean age, sex, and Markwalder score were not significantly different among groups. The mean concentration of VEGF, MMP-2, and MMP-9 were significantly higher in hematoma fluid than in serum (p<0.01). The level of pro-MMP-2 was higher in hematoma fluid (p<0.01). Measurement of MMP-9 showed both pro and active forms in both groups, but levels were higher in hematoma fluid (p<0.01 and p<0.01, respectively). Mean VEGF concentration was highest in group 1 (21,979.3±1387.3 pg/mL), followed by group 2 (20,060.1±1677.2 pg/mL), group 3 (13,746.5±3529.7 pg/mL), group 4 (7523.2±764.9 pg/mL), and lowest in group 5 (6801.9±618.7 pg/mL). There was a significant correlation between VEGF concentrations and MRI type (r=0.854). The present investigation is the first report showing that the concentrations of MMP-2 and MMP-9 are significantly elevated in hematoma fluid, suggesting that the MMPs/VEGF system may be involved in the angiogenesis of CSDH. We also demonstrate a significant correlation between the concentrations of VEGF and MRI appearance. This finding supports the hypothesis that high VEGF concentration in the hematoma fluid is of major pathophysiological importance in the generation and steady increase of the hematoma volume, as well as the determination of MRI appearance.

Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy

“…Therefore, an excess of VEGF is capable of inducing angiogenesis and excessive vascular permeability, which may contribute to the ongoing rebleeding implicated in CSDH growth [22]. This is supported by correlations between VEGF concentrations and the CSDH imaging subtypes which are thought to reflect increased rebleeding [23, 48]. Further to this, higher levels of VEGF expression in the outer membrane have been associated with a higher probability of CSDH recurrence [53].…”

Elevated blood urea nitrogen is associated with recurrence of post-operative chronic subdural hematoma

“…On the other hand, CSDH was recently suggested to be formed through complex processes including angiogenesis, fibrinolysis and inflammation [ 14 ], and the recurrence of CSDH follows the same process as formation. There is strong evidence to show that vascular endothelial growth factor (VEGF) was related to the generation and steady increase of CSDH fluid volume [ 15 – 17 ] as well as the risk of CSDH recurrence [ 18 ]. Interestingly, Lin et al observed that VEGF expression was positively correlated with BUN [ 19 ].…”

Elevated Blood Urea Nitrogen are associated with Recurrence of post-operative Chronic Subdural Hematoma

“…On the other hand, CSDH was recently suggested to be formatted through complex processes including angiogenesis, fibrinolysis and inflammation [14], and the recurrence of CSDH follows the same process as formation. Strong evidence has been provided that vascular endothelial growth factor (VEGF) was related to the generation and steady increase of CSDH fluid volume [15][16][17] as well as the risk of CSDH recurrence [18]. Interestingly, Lin et al observed VEGF expression was positively correlated with BUN [19].…”