Brain venous hypertension induces angiogenesis through overexpression of hypoxia-inducible factor-1 (HIF-1)

Introduction

Brain venous hypertension is present in many cerebrovascular diseases such as arteriovenous malformation. However, how venous hypertension worsens vascular abnormality is unclear. Hypoxia-inducible factor 1 (HIF-1) is an upstream activator of many adaptive responses to tissue. Although decreased O₂ delivery is the well-known stimulus, recent evidence points to a direct mechanical effect to activate HIF-1. This effect has been recently described in chondrocytes, subject to joint motion. Inflammatory cytokines, such as the inteleukins (IL), induce angiogenic factors such as vascular endothelial growth factor (VEGF) and function as tumor and endothelial cell growth factors. Current study was to investigate the modest non-ischema degree of venous hypertension affects the expression of HIF-1α and the changes parallels to the levels of IL-6.

Methods

To establish a non-ischemic venous hypertension model mimicking the hemodynamic changes in human AVM, we have recently implemented the rat model described by ¹ (Ref). Four groups (n=6 per group) of adult Spring-Dowley rat weighting 300 to 350 underwent 1) common carotid artery (CCA) occlusion alone; 2) CCA and external jugular vein (EJV) anastomosis alone; 3) CCA and EJV anastomosis plus transverse sinus and sagittal sinus (TS/SS) occlusion (Fistula+Sinus Occlusion); and 4) sham group. Mean arterial pressure (MAP), sagittal sinus pressure (SSP), surface cerebral blood flow (using a laser Doppler flowmetry, LDF sCBF), and the diameter of CCA and EJV were examined before and after surgery procedure.

Results

There were no differences in mean blood pressure and sCBF before and after surgery among the four groups. Western blot analysis showed that expression of HIF-1α was increased in the brain venous hypertension rats compared to the other three groups (1.8±0.3 vs. 1.1±0.2, 1.2±0.2, and 1±0.1; respectively, p<0.05). Immunohistochemistry shows that HIF-1 positive staining was mainly observed in microvessels located parasagittally, in rat brain cortex and sub-cortex. Under higher magnification, HIF-1α positive staining appeared localized to the cell nuclei. Further study verified that interleukin-6 (IL-6) was also increased in the brain venous hypertension rats, which paralleled to the HIF-1 expression (IL-6: 149±17 pg/ml vs. 112±10, 118±22, and 122±10 pg/ml; respectively, p<0.05).

Conclusion

Non-ischemic venous hypertension induced HIF-1α and the presumably downstream signal, IL-6, both of which may play an important role in pathological angiogenesis. Brain venous hypertension has an intrinsic pro-angiogenic character, which may be independent of its potential to induce tissue ischemia.