PDGF/VEGF system activation and angiogenesis following initial post ovariectomy meningeal microvessel loss.

Recently we demonstrated that cessation of ovarian hormone production causes dramatic vascular remodeling in meningeal microvascular networks characterized by a significant microvessel loss. Further, even two months post ovariectomy (OVX), dura mater microvessels remain destabilized due to a decline in estrogen-mediated angiopoietin-1 (Ang-1) expression and Ang-1/Tie-2 signaling. Such destabilized microvessels could be susceptible to either further regression or angiogenesis. In this study, we tested the hypothesis that initial estrogen-dependent loss of meningeal microvessels following OVX triggers stromal and vascular hypoxic responses aiming at restoring dura microvasculature. We demonstrate that two months post OVX, there is an activation of the hypoxia-inducible factor-1alpha (HIF-1alpha) and PDGF/VEGF system in the dura mater stroma and microvasculature of experimental animals accompanied by a shift in the balance between PI3K and PLCgamma activity downstream of PDGF/VEGF signaling toward PI3K. It appears that the latter serves as a molecular switch favoring angiogenic responses rather than further regression of destabilized microvessels. Indeed, consistent with this idea, we have found a considerable angiogenic activity in meningeal microvascular networks that previously underwent regression. These results indicate that angioadaptation of meningeal microvessels in response to cessation of ovarian hormone production is not a unidirectional, but a very complex multi-stage process regulated on many levels. The implication of this study is that therapeutic interventions, including estrogen-based hormone replacement therapy, with physiological angioadaptation in postmenopausal or post OVX women need to be approached with the extreme caution.