title: Pulsed estrogen therapy prevents post-OVX porcine dura mater microvascular network weakening via a PDGF-BB-dependent mechanism.
abstract: In postmenopausal women, estrogen (E2) deficiencies are frequently associated with higher risk of intracranial hemorrhage, increased incidence of stroke, cerebral aneurysm, and decline in cognitive abilities. In younger postpartum women and those using oral contraceptives, perturbations in E2 are associated with higher risk of cerebral venous thrombosis. A number of serious intracranial pathologic conditions linked to E2 deficiencies, such as dural sinus thrombosis, dural fistulae, non-parenchymal intracranial hemorrhages, migraines, and spontaneous cerebrospinal fluid leaks, involve the vessels not of the brain itself, but of the outer fibrous membrane of the brain, the dura mater (DM). The pathogenesis of these disorders remains mysterious and how estrogen regulates structural and functional integrity of DM vasculature is largely unknown. Here, we demonstrate that post ovariectomy (OVX) DM vascular remodeling is manifested by microvessel destabilization, capillary rarefaction, increased vascular permeability, and aberrant angio-architecture, and is the result of disrupted E2-regulated PDGF-BB signaling within dura microvasculature. These changes, associated with the reduction in systemic PDGF-BB levels, are not corrected by a flat-dose E2 hormone replacement therapy (HRT), but are largely prevented using HRT schedules mimicking physiological E2 fluctuations. We demonstrate that 1) E2 regulates PDGF-BB production by endothelial cells in a dose-dependent manner and 2) optimization of PDGF-BB levels and induction of robust PDGF-mediated endothelial cell-vascular pericyte interactions require high (estrous) E2 concentrations. We conclude that high (estrous) levels of E2 are important in controlling PDGF-mediated crosstalk between endothelial cells and pericytes, a fundamental mechanism governing microvessel stability and essential for preserving intracranial homeostasis.
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States of America ; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States of America ; Center for Gender Physiology and Environmental Adaptation, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Glinskii
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States of America ; Center for Gender Physiology and Environmental Adaptation, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Virginia H
authors.initials: VH
authors.lastname: Huxley
authors.affiliation: Yale Medical School, New Haven, Connecticut, United States of America.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Glinskii
authors.affiliation: Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States of America ; Center for Gender Physiology and Environmental Adaptation, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Leona J
authors.initials: LJ
authors.lastname: Rubin
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States of America ; Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, United States of America ; Center for Gender Physiology and Environmental Adaptation, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Glinsky
mesh_terms: D000818:Animals; D000077214:Becaplermin; D004388:Dura Mater / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004967:Estrogens / Q000172:deficiency / Q000627:therapeutic use; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D008833:Microcirculation / Q000187:drug effects*; D055806:Microvessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D004967:Estrogens; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin