title: Exposure to experimental preeclampsia in mice enhances the vascular response to future injury.
abstract: Cardiovascular disease (CVD) remains the leading killer of women in developed nations. One sex-specific risk factor is preeclampsia, a syndrome of hypertension and proteinuria that complicates 5% of pregnancies. Although preeclampsia resolves after delivery, exposed women are at increased long-term risk of premature CVD and mortality. Pre-existing CVD risk factors are associated with increased risk of developing preeclampsia but whether preeclampsia merely uncovers risk or contributes directly to future CVD remains a critical unanswered question. A mouse preeclampsia model was used to test the hypothesis that preeclampsia causes an enhanced vascular response to future vessel injury. A preeclampsia-like state was induced in pregnant CD1 mice by overexpressing soluble fms-like tyrosine kinase-1, a circulating antiangiogenic protein that induces hypertension and glomerular disease resembling human preeclampsia. Two months postpartum, soluble fms-like tyrosine kinase-1 levels and blood pressure normalized and cardiac size and function by echocardiography and renal histology were indistinguishable in preeclampsia-exposed compared with control mice. Mice were then challenged with unilateral carotid injury. Preeclampsia-exposed mice had significantly enhanced vascular remodeling with increased vascular smooth muscle cell proliferation (180% increase; P<0.01) and vessel fibrosis (216% increase; P<0.001) compared with control pregnancy. In the contralateral uninjured vessel, there was no difference in remodeling after exposure to preeclampsia. These data support a new model in which vessels exposed to preeclampsia retain a persistently enhanced vascular response to injury despite resolution of preeclampsia after delivery. This new paradigm may contribute to the substantially increased risk of CVD in woman exposed to preeclampsia.
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.).
authors.forename: Dafina
authors.initials: D
authors.lastname: Pruthi
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.).
authors.forename: Eliyahu V
authors.initials: EV
authors.lastname: Khankin
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Blanton
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.).
authors.forename: Mark
authors.initials: M
authors.lastname: Aronovitz
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.).
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Burke
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.).
authors.forename: Amy
authors.initials: A
authors.lastname: McCurley
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.). ijaffe@tuftsmedicalcenter.org sananth@bidmc.harvard.edu.
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.affiliation: From the Molecular Cardiology Research Institute (D.P., R.M.B., M.A., A.M., I.Z.J.) and Division of Cardiology, Department of Medicine (R.M.B., I.Z.J.), Tufts Medical Center, Boston, MA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.V.K., S.D.B., S.A.K.); and Howard Hughes Medical Institute, Chevy Chase, MD (S.D.B., S.A.K.). ijaffe@tuftsmedicalcenter.org sananth@bidmc.harvard.edu.
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D049590:Postpartum Period; D011225:Pre-Eclampsia / Q000000981:diagnostic imaging / Q000503:physiopathology*; D011247:Pregnancy; D011270:Pregnancy, Animal; D020127:Recovery of Function; D014463:Ultrasonography; D066253:Vascular Remodeling
keywords: VEGF receptor flt-1 protein; cardiovascular diseases; hypertension; preeclampsia; vascular remodeling