Natriuretic peptides (NPs) regulate blood pressure and fluid balance via their diuretic, natriuretic, and vasoactive properties, and are biomarkers of heart failure in adults and children. Infants with patent ductus arteriosus (PDA) have increased ANP and BNP levels due to cardiac overload. NP levels normalize soon after PDA treatment. These findings suggest that NPs primarily reflect cardiac status, but we speculate that ongoing elevation of NPs in the presence of PDA could augment DA relaxation and create a feed-forward mechanism to further inhibit DA closure. Our observation that NPs induce DA dilation prompts further speculation that NP administration may be a novel approach to maintain patency of the postnatal DA. Little information exists on the role of NPs in DA development or as mediators of DA tone. Our preliminary data show that the Npr1, Npr2, and Npr3 receptors are differentially expressed in the fetal and newborn mouse DA. Exposure of the isolated fetal mouse DA to different NPs produced dose-dependent dilation to CNP>ANP>BNP under fetal and newborn oxygen conditions. Moreover, mice with PDA have elevated circulating NP levels. We hypothesize that: 1) NPs mediate relaxation of the DA and may prolong patency of the postnatal DA, and 2) elevated postnatal NP levels due to PDA and secondary congestive heart failure help to maintain the DA in a non-contractile state. This hypothesis will be examined in three specific aims.
Aim 1 will determine the expression pattern of NPs and their receptors in the fetal and newborn DA, in mouse models of PDA, and cultured DA cells.
Aim 2 will determine, in vitro, NP-induced changes in the tone of DAs from: wild type (preterm vs. term) mice, wild type mice treated with NP antagonists, Npr1 (-/-) and Npr2 (-/-) mice, mice with a PDA phenotype (COX-1(-/-) /COX-2(-/-) and COX-inhibited mice), and the closed DA of postnatal P1 and P2 mice. cGMP production and receptor affinity will be determined.
Aim 3 will determine, in vivo: the response of term newborns exposed to NPs (to prevent postnatal closure);the response to fetal exposure to NP receptor antagonists (to induce fetal DA constriction);and the effect of NP antagonists on mouse models of PDA (to induce PDA constriction in neonates). These studies will provide new information on novel roles for NPs as DA mediators and identify new potential therapeutic targets for modulation of DA tone.

Public Health Relevance

The ductus arteriosus is a fetal blood vessel whose patency is critical for survival in the womb due to its role in transmitting oxygenated blood from the placenta to fetal organs and tissues. Abnormal constriction of this vessel in the fetus or failure to properly close in the newborn is harmful, particularly in premature newborns, but the mechanisms that regulate this vessel are poorly understood. This proposal will test the hypothesis that natriuretic peptides, signaling molecules that are important for fluid balance and blood pressure control, play a significant role in regulation of the normal ductus arteriosus, and contribute to pathological states where the ductus arteriosus fails to constrict after birth.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Kaltman, Jonathan R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
Kraemer, Maria P; Choi, Hyehun; Reese, Jeff et al. (2016) Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1. Vascul Pharmacol 84:47-54
Hooper, Christopher W; Delaney, Cassidy; Streeter, Taylor et al. (2016) Selective serotonin reuptake inhibitor exposure constricts the mouse ductus arteriosus in utero. Am J Physiol Heart Circ Physiol 311:H572-81
Reese, Jeff; Laughon, Matthew M (2015) The Patent Ductus Arteriosus Problem: Infants Who Still Need Treatment. J Pediatr 167:954-6
Pfaltzgraff, Elise R; Shelton, Elaine L; Galindo, Cristi L et al. (2014) Embryonic domains of the aorta derived from diverse origins exhibit distinct properties that converge into a common phenotype in the adult. J Mol Cell Cardiol 69:88-96
El-Khuffash, Afif; Jain, Amish; Corcoran, David et al. (2014) Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res 76:238-44
Vucovich, Megan M; Cotton, Robert B; Shelton, Elaine L et al. (2014) Aminoglycoside-mediated relaxation of the ductus arteriosus in sepsis-associated PDA. Am J Physiol Heart Circ Physiol 307:H732-40
Shelton, Elaine L; Ector, Gerren; Galindo, Cristi L et al. (2014) Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone. Physiol Genomics 46:457-66
McKnight, Katherine; Hoang, Hieu D; Prasain, Jeevan K et al. (2014) Neurosensory perception of environmental cues modulates sperm motility critical for fertilization. Science 344:754-7
Shelton, Elaine L; Poole, Stanley D; Reese, Jeff et al. (2013) Omental grafting: a cell-based therapy for blood vessel repair. J Tissue Eng Regen Med 7:421-33
Cotton, Robert B; Shah, Lisa P; Poole, Stanley D et al. (2013) Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism. J Mol Cell Cardiol 59:86-94

Showing the most recent 10 out of 19 publications