A major theme of this Program Project has been the renal-body fluid feedback control system in which the kidneys play a dominant role in the long-term regulation of body fluid volumes and arterial pressure. A common renal abnormality that has been found in all forms of hypertension examined to date, including genetic and experimental models and human essential hypertension is a hypertensive shift in the pressure natriuresis relationship. A major objective of Project II """"""""is to examine the interactions between endothelin, nitric oxide, oxidative stress and novel anti-angiogenic factors in mediating the reduction in renal-pressure natriuresis in a specific form of hypertension associated with endothelial dysfunction?preeclampsia (PE). Hypertension associated with PE develops during pregnancy and remits after parturition implicating the placenta as a central culprit in the disease. The initiating event in PE is postulated to involve reduced placental perfusion that leads to widespread maternal vascular endothelial dysfunction by mechanisms that remain to be elucidated. Recent studies in preeclamptic women have demonstrated increased placental and circulating concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), a naturally occurring antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). Increased sFlt-1 during preeclampsia is associated with decreased free plasma VEGF and PIGF. Moreover, adenovirus mediated administration of sFlt-1 to pregnant rats to mimic plasma concentrations observed in preeclamptic women, decreases free VEGF and PIGF and produces hypertension and proteinuria. Although these novel findings implicate sFlt-1 in the pathogenesis of hypertension during preeclampsia, what remains unclear are the specific mechanisms that lead to excess sFlt- 1 production and the mechanisms whereby sFlt-1 increases blood pressure during pregnancy. Based on our preliminary data, we propose to test the central hypothesis that reduced uterine perfusion pressure (RUPP) in the pregnant rat increases placental sFlt-1 via ANGII and TNF-ct dependent mechanisms. The increase in plasma concentration of sFlt-1, in turn results in decreased plasma concentrations of VEGF and PIGF. In addition, we propose that chronic sFlt-1 excess during pregnancy impairs renal function and increases total peripheral resistance and blood pressure by decreasing plasma concentrations of free VEGF and PIGF which contribute to endothelial cell dysfunction marked by enhanced production of ET-1, ROS and decreased NO. To test this hypothesis arterial pressure, renal, hormonal, and endothelial factors will be examined in a conscious, chronically instrumented rat model of PE produced by long-term RUPP. In addition to the RUPP model, a sFlt-1 model of PE will be used to determine the interaction between sFlt-1 and ET-1, ROS, and NO production while an in vitro placental explant model will be used to examine the direct interaction between hypoxia and placental sFlt-1, ANGII, and TNF-a production.
Specific aims are: 1) To test the hypothesis that reduced uterine perfusion in pregnant rats increases plasma concentrations and placental levels of sFlt-1 via ANGII and TNF-a dependent mechanisms 2) To test the hypothesis that chronic sFlt-1 excess in pregnant rats causes hypertension and a chronic hypertensive shift in the pressure-natriuresis relationship by reducing renal blood flow and GFR 3) To test the hypothesis that enhanced formation of ET-1 and decreased levels of NO mediate the reduction in renal function and elevation in arterial pressure that occurs during chronic sFlt-1 excess in pregnant rats. 4) To test the hypothesis that enhanced formation of reactive oxygen species mediate the reduction in renal function and elevation in arterial pressure that occurs during chronic sFlt-1 excess in pregnant rats.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL051971-19
Application #
8374556
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
19
Fiscal Year
2012
Total Cost
$283,761
Indirect Cost
$92,029
Name
University of Mississippi Medical Center
Department
Type
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Jung, Mira; Ma, Yonggang; Iyer, Rugmani Padmanabhan et al. (2017) IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol 112:33
Ma, Yonggang; Iyer, Rugmani Padmanabhan; Jung, Mira et al. (2017) Cardiac Fibroblast Activation Post-Myocardial Infarction: Current Knowledge Gaps. Trends Pharmacol Sci 38:448-458
Feng, Ruiqi; Liu, Jia; Wang, Zhenhua et al. (2017) The structure-activity relationship of ginsenosides on hypoxia-reoxygenation induced apoptosis of cardiomyocytes. Biochem Biophys Res Commun 494:556-568
Muntner, Paul; Abdalla, Marwah; Correa, Adolfo et al. (2017) Hypertension in Blacks: Unanswered Questions and Future Directions for the JHS (Jackson Heart Study). Hypertension 69:761-769
Chade, Alejandro R (2017) Small Vessels, Big Role: Renal Microcirculation and Progression of Renal Injury. Hypertension 69:551-563
Drummond, Heather A; Xiang, Lusha; Chade, Alejandro R et al. (2017) Enhanced maximal exercise capacity, vasodilation to electrical muscle contraction, and hind limb vascular density in ASIC1a null mice. Physiol Rep 5:
Faulkner, Jessica L; Amaral, Lorena M; Cornelius, Denise C et al. (2017) Vitamin D supplementation reduces some AT1-AA-induced downstream targets implicated in preeclampsia including hypertension. Am J Physiol Regul Integr Comp Physiol 312:R125-R131
Blair, Evan T; Clemmer, John S; Harkey, H Louis et al. (2017) Physiologic Mechanisms of Water and Electrolyte Disturbances After Transsphenoidal Pituitary Surgery. World Neurosurg 107:429-436
Bakrania, Bhavisha A; Spradley, Frank T; Satchell, Simon C et al. (2017) Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells. Am J Physiol Regul Integr Comp Physiol :
Taylor, Erin B; Ryan, Michael J (2017) Immunosuppression With Mycophenolate Mofetil Attenuates Hypertension in an Experimental Model of Autoimmune Disease. J Am Heart Assoc 6:

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