The ovarian hormone, relaxin, is an important signal causing profound renal and systemic vasodilation, as well as increased arterial compliance in the maternal circulation during normal pregnancy. These changes are important for both initiating and accommodating increased maternal blood volume and flow that, in turn, support fetal growth. When circulating relaxin is deficient in pregnancy, renal and systemic arterial adaptations are compromised. Given its prominent role in the arterial changes of normal pregnancy, it is important to understand the mechanisms of relaxin action in the vasculature. Such understanding has the potential to explain dysregulation of vasodilation and arterial compliance during preeclampsia in which fetal growth is frequently compromised. Ultimately, vasodilation by relaxin depends on endothelial nitric oxide that relaxes the underlying vascular smooth muscle. The overarching hypothesis of this grant proposal is that the vasodilatory actions of relaxin hinge on bi-directional communication between the vascular smooth muscle and the endothelium. Preliminary data indicate that the major relaxin receptor, Lgr7, mediates the renal vasodilatory and arterial compliances changes of relaxin. Surprisingly, however, further preliminary results show substantially more Lgr7 receptor in vascular smooth muscle than endothelium. Thus, the first Hypothesis and Specific Aim address whether it is the Lgr7 receptor in the vascular smooth muscle that mediates the renal vasodilatory and arterial compliances changes of relaxin. Mice with conditional knock-out of the Lgr7 from the vascular smooth muscle will be generated, in order to test whether the renal vasodilatory and arterial compliance changes of relaxin are abolished in these mice. The second Hypothesis and Specific Aim address the molecular intermediate(s) stimulated by relaxin in the vascular smooth muscle that, in turn, communicate with the endothelium. In this respect, new and exciting preliminary data implicate vascular endothelial growth factor. As well, the second Hypothesis and Specific Aim address the molecular intermediate(s) stimulated in the endothelium leading to increased NO activity. These Hypotheses and Specific Aims will be interrogated by studying the function of small renal and subcutaneous arteries isolated from mice and humans, respectively, as well as renal blood flow and arterial pressure in conscious mice. This project is ideally suited to the R21 funding mechanism because it is exploratory, testing a novel mechanistic model of relaxin action in the renal circulation, proposes a new methodological approach to testing this mechanistic model in vivo that is in need of development (targeted gene knock-out mice), and last, but not least, will facilitate the therapeutic application of relaxin (or relaxin mimetic) as a vasodilator and modifier of arterial compliance. Indeed, the fundamental importance of relaxin in the cardiovascular adaptations of normal pregnancy holds promise for the effectiveness of pharmacologic manipulation of relaxin signaling in conditions of pathophysiological cardiovascular dysregulation in pregnancy.

Public Health Relevance

A hormone from the ovary called relaxin is a key signal that acts on blood vessels to increase maternal blood flow during normal pregnancy that is important to support fetal growth. We propose to find out how relaxin affects blood vessels to cause this change. It is important to understand the mechanisms of action of relaxin in blood vessels for two main reasons: (i) it will help us understand abnormal pregnancy such as preeclampsia in which the major problem is decreased maternal blood flow, and (ii) it is necessary for potential use of relaxin as a therapeutic agent to treat various blood vessel diseases in the pregnant and nonpregnant populations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL093605-01A2
Application #
7738676
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Barouch, Winifred
Project Start
2009-08-01
Project End
2011-06-30
Budget Start
2009-08-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$236,625
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Kaftanovskaya, Elena M; Huang, Zaohua; Lopez, Carolina et al. (2015) Conditional deletion of the relaxin receptor gene in cells of smooth muscle lineage affects lower reproductive tract in pregnant mice. Biol Reprod 92:91
Takeo, Toru; Horikoshi, Yuka; Nakao, Satohiro et al. (2015) Cysteine analogs with a free thiol group promote fertilization by reducing disulfide bonds in the zona pellucida of mice. Biol Reprod 92:90
Conrad, Kirk P; Davison, John M (2014) The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin? Am J Physiol Renal Physiol 306:F1121-35
McGuane, Jonathan T; Danielson, Leslie A; Debrah, Julianna E et al. (2011) Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans. Hypertension 57:1151-60
Conrad, Kirk P (2011) Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin Nephrol 31:15-32
Conrad, Kirk P (2010) Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension 56:2-9