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Emerging Role of Relaxin in the Maternal Adaptations to Normal Pregnancy: Implications for Preeclampsia

  • Kirk P. Conrad
    Correspondence
    Address reprint requests to Kirk P. Conrad, MD, Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Road, M552, PO Box 100274, Gainesville, FL 32610
    Affiliations
    Department of Physiology and Functional Genomics, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL; and the D.H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, FL
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      Summary

      Relaxin is an approximately 6-kilodalton peptide hormone secreted by the corpus luteum, and circulates in the maternal blood during pregnancy. Relaxin administration to awake, chronically instrumented, nonpregnant rats mimics the vasodilatory phenomena of pregnancy. Furthermore, immunoneutralization of relaxin or its elimination from the circulation during midterm pregnancy in awake rats prevents maternal systemic and renal vasodilation, and the increase in global arterial compliance. Human investigation, albeit limited through 2010, also reveals vasodilatory effects of relaxin in the nonpregnant condition and observations consistent with a role for relaxin in gestational renal hyperfiltration. Evidence suggests that the vasodilatory responses of relaxin are mediated by its major receptor, the relaxin/insulin-like family peptide 1 receptor, RFXP1. The molecular mechanisms of relaxin vasodilation depend on the duration of hormone exposure (ie, there are rapid and sustained vasodilatory responses). Newly emerging data support the role of Gαi/o protein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase in the rapid vasodilatory responses of relaxin. Sustained vasodilatory responses critically depend on vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. Gelatinases hydrolyze big endothelin (ET) at a gly-leu bond to form ET1-32, which activates the endothelial ETB/nitric oxide vasodilatory pathway. Although the relevance of relaxin biology to preeclampsia is largely speculative at this time, there are potential tantalizing links that are discussed in the context of our current understanding of the etiology and pathophysiology of the disease.

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