Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone.
Failure of the ductus arteriosus (DA) to close at birth can lead to serious complications. Conversely, certain profound congenital cardiac malformations require the DA to be patent until corrective surgery can be performed. In each instance, clinicians have a very limited repertoire of therapeutic options at their disposal - indomethacin or ibuprofen to close a patent DA (PDA) and prostaglandin E1 to maintain patency of the DA. Neither treatment is specific to the DA and both may have deleterious off-target effects. Therefore, more therapeutic options specifically targeted to the DA should be considered. We hypothesized the DA possesses a unique genetic signature that would set it apart from other vessels. A microarray was used to compare the genetic profiles of the murine DA and ascending aorta (AO). Over 4,000 genes were differentially expressed between these vessels including a subset of ion channel-related genes. Specifically, the alpha and beta subunits of large-conductance calcium-activated potassium (BKCa) channels are enriched in the DA. Gain- and loss-of-function studies showed inhibition of BKCa channels caused the DA to constrict, while activation caused DA relaxation even in the presence of O2. This study identifies subsets of genes that are enriched in the DA that may be used to develop DA-specific drugs. Ion channels that regulate DA tone, including BKCa channels, are promising targets. Specifically, BKCa channel agonists like NS1619 maintain DA patency even in the presence of O2 and may be clinically useful.
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee; Elaine.L.Shelton@vanderbilt.edu.
Elaine L
EL
Shelton
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee;
Gerren
G
Ector
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
Cristi L
CL
Galindo
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee;
Christopher W
CW
Hooper
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee;
Naoko
N
Brown
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee;
Irene
I
Wilkerson
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee;
Elise R
ER
Pfaltzgraff
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee;
Bibhash C
BC
Paria
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee;
Robert B
RB
Cotton
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Jason Z
JZ
Stoller
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee;
Jeff
J
Reese
D000818:Animals; D004373:Ductus Arteriosus / Q000378:metabolism*; D004374:Ductus Arteriosus, Patent / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D059467:Transcriptome; D014654:Vascular Patency / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics
D007473:Ion Channels
BKCa; PDA; ductus arteriosus; ion channels; vascular tone