title: Elevated blood pressure in preterm-born offspring associates with a distinct antiangiogenic state and microvascular abnormalities in adult life.
abstract: Preterm-born individuals have elevated blood pressure. We tested the hypothesis that this associates with an enhanced antiangiogenic circulating profile and that this association is mediated by variations in capillary density. We studied 204 adults aged 25 years (range, 20-30 years), of which 102 had been followed up prospectively since very preterm birth (mean gestational age, 30.3±2.5 weeks) and 102 were born term to uncomplicated pregnancies. A panel of circulating biomarkers, including soluble endoglin and soluble fms-like tyrosine kinase-1, were compared between groups and related to perinatal history and adult cardiovascular risk. Associations with cardiovascular phenotype were studied in 90 individuals who had undergone detailed assessment of microvascular, macrovascular, and cardiac structure and function. Preterm-born individuals had elevations in soluble endoglin (5.64±1.03 versus 4.06±0.85 ng/mL; P<0.001) and soluble fms-like tyrosine kinase-1 (88.1±19.0 versus 73.0±15.3 pg/mL; P<0.001) compared with term-born individuals, proportional to elevations in resting and ambulatory blood pressure, as well as degree of prematurity (P<0.05). Maternal hypertensive pregnancy disorder was associated with additional increases in soluble fms-like tyrosine kinase-1 (P=0.002). Other circulating biomarkers, including those of inflammation and endothelial activation, were not related to blood pressure. There was a specific graded association between soluble endoglin and degree of functional and structural capillary rarefaction (P=0.002 and P<0.001), and in multivariable analysis, there were capillary density-mediated associations between soluble endoglin and blood pressure. Preterm-born individuals exhibit an enhanced antiangiogenic state in adult life that is specifically related to elevations in blood pressure. The association seems to be mediated through capillary rarefaction and is independent of other cardiovascular structural and functional differences in the offspring.
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Lewandowski
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Esther F
authors.initials: EF
authors.lastname: Davis
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Grace
authors.initials: G
authors.lastname: Yu
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Janet E
authors.initials: JE
authors.lastname: Digby
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Henry
authors.initials: H
authors.lastname: Boardman
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Polly
authors.initials: P
authors.lastname: Whitworth
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Atul
authors.initials: A
authors.lastname: Singhal
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Alan
authors.initials: A
authors.lastname: Lucas
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Kenny
authors.initials: K
authors.lastname: McCormick
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.).
authors.forename: Angela C
authors.initials: AC
authors.lastname: Shore
authors.affiliation: From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.J.L., E.F.D., G.Y., J.E.D., H.B., P.W., P.L.); Department of Clinical Epidemiology, Nutrition and Biostatistics, Institute of Child Health, University College London, London, United Kingdom (A.S., A.L.); Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom (K.M.); and Department of Vascular Medicine, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom (A.C.S.). adam.lewandowski@cardiov.ox.ac.uk paul.leeson@cardiov.ox.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Leeson
mesh_terms: D000328:Adult; D032721:Adult Children; D015703:Antigens, CD / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000453:epidemiology; D000071063:Endoglin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000503:physiopathology*; D008297:Male; D055806:Microvessels / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D047928:Premature Birth / Q000503:physiopathology*; D015995:Prevalence; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000097:blood; D012307:Risk Factors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: blood pressure; capillaries; hypertension, pregnancy-induced; infant, premature; microcirculation; premature birth