Abstract
Our recent results demonstrate that cessation of ovarian hormone production causes dramatic meningeal microvascular network remodeling, characterized by significant capillary rarefaction. Even 2 months post-ovariectomy (OVX) pig dura mater microvessels remain destabilized due to reduced angiopoietin-1 expression. From this state either further regression or angiogenesis could occur. We tested the hypothesis that initial estrogen-dependent meningeal microvessel loss following OVX triggers stromal and vascular hypoxic responses aimed at restoring dura microvasculature. We demonstrate that 2 months post-OVX there is activation of the PDGF/VEGF system in the dura mater stroma and microvasculature that is accompanied by a shift in the balance between PI3K and PLCγ 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 the destabilized microvessels. Consistent with this idea we have found considerable angiogenic activity in meningeal microvascular networks that underwent previous regression. Our results indicate that angioadaptation of meningeal microvessels in response to cessation of ovarian hormone production is not a unidirectional, but a complex multistage process regulated on multiple levels. Supported by: AHA Heartland Affiliate Postdoctoral Fellowship.
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