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Principal Investigator: Maxwell T Frankfurter
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $53,974
Funding agency: National Heart Lung and Blood Institute
Project Summary
The placenta is a transient, vascular organ necessary for in utero gas, nutrient, waste exchange in the majority
of mammals. Placental dysfunction may lead to hypertensive disorders of pregnancy, fetal growth restriction, or
intrauterine fetal demise in humans. In mice and humans, congenital cardiac defects are associated with
placental insufficiency. In mice, endothelial cells from the allantois generate a highly branched exchange
interface with the maternal circulation in a region termed the labyrinth. The molecular pathways that pattern the
labyrinth remain poorly characterized. As the embryo develops, its metabolic demands change, and the
number of placental vessels appears to increase accordingly. However, signals from the embryo proper that
may communicate its oxygen and nutritional requirements remain obscure. I have deleted Endoglin (Eng), an
endothelial BMP10 co-receptor, in the labyrinth using Hoxa13-Cre and found it to be lethal in midgestation.
BMP10, secreted by the developing heart and liver, acts on ENG and the TGF-β/BMP type I receptor ALK1 on
ECs to promote activation of SMAD1/5/8. Histologically, Eng mutant placentas have fewer, narrower fetal
vessels than controls, and these vessels appear poorly perfused. Therefore, I hypothesize that ENG and ALK1
in placental ECs function to promote angiogenesis in response to BMP10 secreted by cardiomyocytes.
Through this project, I will use in vivo mouse genetic tools to understand the function of ENG in the labyrinth,
as well as assess the requirement for a BMP10 signal from the embryo to instruct placental vascularization. In
aim 1, I will identify the primary deficit in Hoxa13-Cre; Eng fl/- placentas through morphometric, histologic, and
transcriptomic analyses. In aim 2, I will determine whether ENG, along with ALK1, promotes activation of
SMAD1/5/8 in placental ECs in response to cardiac-derived BMP10. Together, these experiments will enhance
our understanding of how placental development is regulated and informed by the embryo proper, which may
have implications for placental insufficiency and congenital heart disease in humans.
Terms: <ACVRL1><ACVRL1 gene><ACVRLK1><ACVRLK4><ALK-1><Activin A Receptor, Type II-Like Kinase 1 Gene><Activin Receptor-Like Kinase 1 Gene><Affect><Affinity><Arteriovenous Angioma><Arteriovenous Hemangioma><Arteriovenous malformation><BMP type I receptor><BMP-10><BMP10><BMP10 gene><BMPR-I><Blood Vessels><Body Tissues><Bone Morphogenetic Protein 10><Bone-Derived Transforming Growth Factor><CD105 Antigen><Cardiac><Cardiac Malformation><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells Placenta-Tissue><Cellular Function><Cellular Physiology><Cellular Process><Circulation><Communication><Cone><Congenital Cardiac Defects><Congenital Heart Defects><Data><Defect><Development><Disease><Disorder><Dysfunction><EPH Gestosis><Embryo><Embryonic><Endocrine><Endoglin><Endothelial Cells><Endothelium><Fetal Growth Restriction><Fetal Growth Retardation><Functional disorder><Gases><Gene Transcription><Generalized Growth><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Geometry><Gestation><Goals><Growth><HHT2><Heart><Heart Malformation><Heart Muscle Cells><Heart myocyte><Hereditary hemorrhagic telangiectasia><Histologic><Histologically><Human><Hypertension><IUGR><Image><Impairment><In Vitro><Internal Ear><Intracellular Communication and Signaling><Intrauterine Growth Retardation><Labyrinth><Ligands><Liver><Location><Mammalia><Mammals><Measures><Mediating><Metabolic><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><Normal Placentoma><Nutrient><Nutritional Requirements><O element><O2 element><ORW2><Organ><Osler-Rendu Disease><Osler-Weber-Rendu Disease><Oxygen><Pathology><Pathway interactions><Pattern><Perfusion><Phenocopy><Phenotype><Phosphorylation><Physiopathology><Placenta><Placenta Embryonic Tissue><Placental Circulation><Placental Development><Placental Insufficiency><Placentation><Placentome><Platelet Transforming Growth Factor><Population><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Toxemias><Process><Protein Phosphorylation><Proteinuria-Edema-Hypertension Gestosis><RNA Expression><Racemose Angioma><Racemose Hemangioma><Receptor Protein><Role><SKR3><Secondary to><Shapes><Side><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Subcellular Process><TGF B><TGF-beta><TGF-β><TGFBR1><TGFBR1 gene><TGFbeta><TGFβ><Testing><Tissue Growth><Tissues><Transcription><Transforming Growth Factor P Receptor III><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Umbilical Cord><Umbilical cord structure><Vascular Endothelial Cell><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascularization><abnormal heart development><allantois><angiogenesis><biological signal transduction><bone morphogenetic protein receptor type I><cardiomyocyte><congenital cardiac abnormality><congenital cardiac anomalies><congenital cardiac disease><congenital cardiac disorder><congenital cardiac malformation><congenital heart abnormality><congenital heart anomaly><congenital heart disease><congenital heart disorder><congenital heart malformation><developmental><experiment><experimental research><experimental study><experiments><fetal><genome mutation><hepatic body system><hepatic organ system><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><imaging><impaired fetal growth><improved><in utero><in vivo><inner ear><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth restriction><mouse genetics><mutant><nutrient requirement><ontogeny><pathophysiology><pathway><pre-eclamptic><pregnancy disorder><pregnancy toxemia/hypertension><prenatal growth disorder><receptor><response><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><tool><transcriptomics><vascular><vascular bed><wasting>