Placental Stem Villus Arterial Remodeling Associated with Reduced Hydrogen Sulfide Synthesis Contributes to Human Fetal Growth Restriction.
Intrauterine fetal growth restriction (IUGR) is often associated with compromised umbilical arterial flow, indicating increased placental vascular resistance. Oxidative stress is causatively implicated. Hydrogen sulfide maintains differentiated smooth muscle in vascular beds, and its synthetic enzyme cystathionine-γ-lyase (CSE) is down-regulated in growth-restricted placentas. We hypothesized that remodeling of resistance arteries in stem villi contributes to IUGR by compromising umbilical blood flow via oxidative stress, reducing hydrogen sulfide signaling. Stem villus arteries in human IUGR placentas displaying absent or reversed end-diastolic flow contained reduced myosin heavy chain, smooth muscle actin, and desmin, and increased markers of dedifferentiation, cellular retinol-binding protein 1, and matrix metalloproteinase 2, compared to term and preterm controls. Wall thickness/lumen ratio was increased, lumen diameter decreased, but wall thickness remained unchanged in IUGR placentas. CSE correlated positively with myosin heavy chain, smooth muscle actin, and desmin. Birth weight correlated positively with CSE, myosin heavy chain, smooth muscle actin, and desmin, and negatively with cellular retinol-binding protein 1 and matrix metalloproteinase 2. These findings could be recapitulated in vitro by subjecting stem villus artery explants to hypoxia-reoxygenation, or inhibiting CSE. Treatment with a hydrogen sulfide donor, diallyl trisulfide, prevented these changes. IUGR is associated with vascular remodeling of the stem villus arteries. Oxidative stress results in reduction of placental CSE activity, decreased hydrogen sulfide production, and smooth muscle cell dedifferentiation in vitro. This vascular remodeling is reversible, and hydrogen sulfide donors are likely to improve pregnancy outcomes.
Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom; Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, Singapore.
Liangjian
L
Lu
Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
John
J
Kingdom
Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom. Electronic address: gjb2@cam.ac.uk.
Graham J
GJ
Burton
Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom. Electronic address: tc269@cam.ac.uk.
Tereza
T
Cindrova-Davies
D000328:Adult; D000498:Allyl Compounds / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D054337:Cell Dedifferentiation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002824:Chorionic Villi / Q000098:blood supply*; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D047928:Premature Birth / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054840:Retinol-Binding Proteins, Cellular / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects
D000498:Allyl Compounds; D003893:Desmin; D012333:RNA, Messenger; D054840:Retinol-Binding Proteins, Cellular; D013440:Sulfides; C042577:diallyl trisulfide; D020778:Matrix Metalloproteinase 2; D018995:Myosin Heavy Chains; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide