Meningeal vascular response to estrogen‐based therapy in post ovariectomized pigs

Abstract

Loss of gonadal function in women is associated with increased incidence of stroke, cranial aneurysms, and neurodegenerative disease. Those sequelae infer that intracranial vascular adaptation at the onset of reproductive senescence confers enhanced cerebrovascular risk. Our data from in vivo pig model show that following ovariectomy (OVX), meningeal vasculature undergoes substantial remodeling characterized by loss of capillaries, increase in average microvessel size and augmented permeability associated with estrogen receptor (ER) alpha dependent decrease in angiopoietin‐1 expression. Even 2 months post OVX, vascular networks remain destabilized and prone to further remodeling. Mechanistically, this process is regulated in part by ER‐related pathways and, therefore, is estrogen‐dependent. However, effects of estrogen (E2) based therapy on such remodeling depend strikingly on the treatment regimen. We show that flat‐dose E2 therapy fails to prevent vascular remodeling, while E2 regimens mimicking natural estrous cycle‐associated E2 fluctuations prevent post OVX microvascular alterations. It appears that, as opposed to conventional flat‐dose regimens, pulsed E2‐based therapy could present a compelling strategy for preventing massive intracranial vascular remodeling during reproductive senescence compromising functional and structural integrity of meningeal microvasculature.Supported by AHA National SDG 0830287N, NIHHL078816, NASA NNJ05HF37G, NIHC06RR017353