Prolactin receptor signaling regulates adaptation of the heart during pregnancy and postpartum

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The heart must continually adapt to a multitude of stimuli and stressors, which are generally divided into pathologic and physiologic categories. Amongst these, the physiologic stress of pregnancy and its aftermath (i.e., the postpartum period of lactation and nursing) are relatively less well understood, and much is unknown about how extra-cardiac signals regulate and coordinate these processes. In a number of diverse maternal tissues, including mammary glands, adipose and pancreatic β-cells, lactogenic hormones, acting via the prolactin receptor (PRLR), activate downstream signal transduction and transcriptional regulation machinery to orchestrate target tissue activity during pregnancy and regression following parturition and nursing. To date, PRLR signaling in the heart during pregnancy has not been studied. The objective of this grant is to establish a role for PRLR in adaptation of the heart to pregnancy and the reversal of gestational changes in the postpartum. We explore the central hypothesis that cardiomyocyte lactogenic signaling, via PRLR, is essential for cardiac adaptation. We will investigate novel physiologic roles of cardiomyocyte lactogenic signaling in two Specific Aims. In Aim 1, we will establish the requirement for cardiomyocyte PRLR signaling in the adaptation of the heart during pregnancy. Similarly, in Aim 2, we will identify a role of cardiomyocyte PRLR signaling in the postpartum reversal of adaptive gestational changes in the heart, during the nursing period when the mother is lactating. To do so, we employ a novel and unique genetic mouse model harboring a cardiomyocyte-specific deletion of PRLR (CM-PRLRKO mice). We examine CM-PRLRKO mice using multiple analyses, including functional (echocardiography), molecular (gene and protein expression), cellular (histologic), and metabolic (radiolabeled isotope tracing) studies. Together, these studies will demonstrate that PRLR is required for normal gestational cardiac remodeling, as well as for the cardioprotective benefits of lactation and breastfeeding, such that absence of PRLR signaling or failure to nurse and lactate will have adverse effects on cardiac function and remodeling. This research is significant because these studies would be the first to establish a physiologic role for PRLR signaling in the adaptive responses of the maternal heart. At a fundamental level, these studies would expand our understanding of the context and molecular mechanisms by which hormones regulate cardiomyocyte function, and may identify novel pathways by which the heart restores itself following acute physiologic stressors.