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AMPK and Akt crosstalk controls dura mater post ovariectomy (OVX) microvascular remodeling in pigs

Microvascular remodeling associated with the onset of reproductive senescence is a complex multi‐step process. Recently, we demonstrated that cessation of ovarian hormone production causes dramatic remodeling of meningeal microvascular networks, characterized by significant capillary rarefaction. However, the initial estrogen‐dependent post OVX loss of microvessels triggers stromal and vascular hypoxic responses leading to an increase in HIF‐1α expression and PDGF/VEGF system activation. Concomitant attenuation of hypoxia‐induced phosphorylation of AMP‐activated protein kinase (AMPK), caused by reduced estrogen (E2) levels, contributes to the activation of Akt and mTOR/p70S6K pathways, thereby promoting enhanced protein synthesis and prompting new vessel growth. Indeed, 2 months post OVX, we observed considerable angiogenic activity in meningeal microvascular networks that underwent previous regression. In summary our results demonstrate that post OVX angioadaptation proceeds through distinct stages regulated tightly on multiple levels by a complex interplay between several major signaling pathways induced by an array of internal and external metabolic stimuli. Supported by: NASA NNJ05HF37G, VA Merit Review Award, and NIH HL078816, HL075186, RR017353.