Children born to women with hypertensive disorders inpregnancy have an elevated risk of developing hypertensive disorders later inlife. The mechanisms for this fetal programming are unclear. We have previouslyidentified a critical role for arginine vasopressin (AVP) in the development ofpreeclampsia. Additionally, we demonstrated differences in the expression ofAVP receptors on circulating cells in women who developed preeclampsia comparedto women who did not experience preeclampsia. Because AVP is a hormone thatfunctions to regulate blood pressure and volume homeostasis, we hypothesizedthat differences in expression of vasopressin receptors and related genes arealso altered in children born to women with preeclampsia. We measured the expression of receptors AVPR1a, AVPR1b, AVPR2, OXTR, and CUL5 as well as LNPEP, the major aminopeptidase that cleavesAVP. Expression in umbilical cord blood cells from women with 1) no hypertensivedisorders in pregnancy (control subjects) (N=20) 2) pregnant women with chronichypertension (N=20) and 3) women with preeclampsia (N=10) in the indexpregnancy were compared. Coded umbilical cord blood cells and associated clinicaldata were obtained from the University of Iowa Maternal Fetal Tissue Bank (IRB#200910784). RNA was purified from the cells and used for real‐time quantitativePCR to assess variation in receptor expression in children born to women withhypertensive disorders of pregnancy relative to control subjects. In childrenborn to women with chronic hypertension, AVPR2 (−8.2 Fold Change), LNPEP (−13Fold Change), CUL5 (−14 Fold Change) AVPR1b (−3.1 Fold Change) and OXTR (−4.3Fold Change) were all significantly under‐expressed with controls. Samples fromchildren born to women with preeclampsia had significantly lower expression of AVPR1a(−4.7 Fold Change), AVPR1b (−2.5 Fold Change), AVPR2 (−2.5 Fold Change), andOXTR (−2.8 Fold Change) when compared to non‐preeclamptic samples. Thesedifferences in gene expression may be related to the future risk ofhypertension later in life for children born to women with hypertensivediseases in pregnancy. In future work, we will interrogate different cellpopulations. In addition, we will determine whether maternal peripheral bloodvasopressin receptor expression correlates with child cord blood receptorexpression. This work was supported by the Iowa Center for Research byUndergraduates (LD), NIH CTSA grant UL1TR002537, American Heart AssociationPostdoctoral Fellowship (SS), and the American Heart Association StrategicallyFocused Research Network Grant (MS, DS, SS). Support or Funding Information This work was supported by the Iowa Center for Research by Undergraduates (LD), NIH CTSA grant UL1TR002537, American Heart Association Postdoctoral Fellowship (SS), and the American Heart Association Strategically Focused Research Network Grant (MS, DS, DB, KW, SS). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Children born to women with hypertensive disorders in pregnancy have an elevated risk of developing hypertensive disorders later in life. The mechanisms for this fetal programming are unclear. Because vasopressin (AVP) is a hormone that functions to regulate blood pressure and volume homeostasis, we hypothesized that differences in expression of vasopressin receptors (AVPRs) and related genes are also altered in children born from preeclampsia-affected pregnancies. We measured the expression of receptors AVPR1a, AVPR1b, AVPR2, OXTR, and CUL5 as well as LNPEP, the major aminopeptidase that cleaves AVP. Expression in umbilical cord blood cells and maternal peripheral blood cells from women with 1) no hypertensive disorders in pregnancy (control subjects) (N=20) 2) pregnant women with chronic hypertension (N=20) and 3) women with preeclampsia (N=10) in the index pregnancy were compared. Coded cell samples and associated clinical data were obtained from the University of Iowa Maternal Fetal Tissue Bank (IRB# 200910784). RNA was purified from the cells and used for real-time quantitative PCR to assess variation in receptor expression in children born to women with hypertensive disorders of pregnancy relative to control subjects. In children born to women with chronic hypertension, AVPR2 (-8.2 Fold Change, P<0.001), LNPEP (-13 Fold Change, P<0.001), CUL5 (-14 Fold Change, P<0.001), AVPR1b (-3.1 Fold Change, P=0.001), and OXTR (-4.3 Fold Change) were all significantly under-expressed when compared to normotensive controls. Samples from children born to women with preeclampsia had significantly lower expression of AVPR1a (-4.7 Fold Change, P<0.001), AVPR1b (-2.5 Fold Change, P=0.045), AVPR2 (-2.5 Fold Change, P=0.001), and OXTR (-2.8 Fold Change, P<0.001) when compared to non-preeclamptic samples. Differences in expression were also mirrored early in pregnancy in maternal blood in women with chronic hypertension. For example, CUL5 and LNPEP were decreased in the first trimester (-3.01 Fold Change, P=0.004 and -3.64 Fold Change P=0.007, respectively). The differences in gene expression in cord blood may be related to the future risk of hypertension later in life for children born to women with hypertensive diseases in pregnancy.

Arginine vasopressin (AVP) has been shown to play a role in preeclampsia, a hypertensive and immune-mediated disorder in pregnancy. Chronic infusion of AVP during gestation into wild-type mice results in the pregnancy-specific physiological changes (hypertension, kidney damage, fetal growth restriction) as well as increased CD4+ T H 1 and T H 17 associated cytokine responses observed in human pregnancies affected by preeclampsia. Further, human CD4+ T cells isolated from preeclamptic women were found to differentially express AVP receptors (AVPRs) 1a and 2 compared to control pregnancies. Abnormalities in other immune cells are seen during preeclampsia, including auto-antibody production (B cells), poor placental development (natural killer (NK) cells), and increased pro-inflammatory T cells responses (via dendritic cells (DC)). We, therefore, hypothesize that B cells, NK cells, and DC express AVPRs. To begin to understand 1) the expression pattern of AVPRs on CD4- lymphocytes and 2) if there are differences in expression between males and females, we evaluated the expression of AVPR 1a, 2, and 1b specifically on B cells, NK cells, and DC. Each subset was purified via negative selection from de-identified human peripheral blood mononuclear cells obtained through Leukocyte Reduction System (LRS) cone donors at the DeGowin Blood Center followed by qPCR for AVPR 1a, 2, and 1b expression (N=6 per cell type). B cells, NK cells, and DC expressed all three AVPRs 1a, 2, and 1b. All three lymphocyte populations showed a lower expression of AVPR1b compared to expression of 1a and 2, with B cells having the lowest expression of AVPR1b (p<0.05). Interestingly, while B cells and NK cells showed no differences in expression based on sex of the donor, DC isolated from male donors more highly expressed AVPR1b compared to female donors (p=0.0035). In conclusion, we demonstrate that B cells, NK cells, and DC highly express AVPR1a and 2, and that DC expression of AVPRs is sex dependent. Further investigation into the utilization of these receptors by these immune cells and the potential impact of sex-specific differences may elucidate newly identified mechanisms of AVP and immune interactions in not only preeclampsia, but possibly other cardiovascular-related diseases as well.

Arginine vasopressin (AVP) is a hormone that functions to regulate blood pressure and bodily fluid homeostasis. Vasopressin has three main receptors AVPR1a, AVPR1b, and AVPR2 which were investigated in this project along with OXTR, LNPEP, and CUL5. AVPR1a functions in the smooth muscle and causes vasoconstriction, AVPR1b functions in the pituitary helping to regulate adrenocorticotropic hormone release, and AVPR2 is expressed highly in the kidneys and works to concentrate urine. This project investigates how these various receptors are expressed with different factors related to pregnancy such as, sex of the baby, chronically hypertensive mothers, and gestational age at delivery