Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia

Abstract

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 Gα(i/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 ET(1-32), which activates the endothelial ET(B)/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.

Figure 1

Serum concentrations of relaxin in the luteal phase of the menstrual cycle and during pregnancy in human beings. Figure 1 is based on data from Szlachter et al, Stewart et al, and O’Byrne et al.

Figure 2

Working model for the sustained vasodilatory responses of relaxin. Inhibitors of relaxin vasodilation are shown in the boxes. GM6001, general MMP inhibitor; RES-701–1, specific ET_B receptor antagonist; SB209670, mixed ET_A and ET_B receptor antagonist; L-NAME, nitro-L-arginine methyl ester; L-NMMA, N^G-monomethyl-L-arginine. Note that phosphoramidon (an inhibitor of the classic ET-converting enzyme), STT (control peptide for cyclic CTT), heat-inactivated TIMP-2, BQ-123 (a specific ET_A-receptor antagonist), D-NAME, and IgGs (control antibodies for MMP neutralizing antibodies) did not affect the slow vasodilatory responses of relaxin. Not depicted in this schema are the roles of the Lgr7 (RXFP1) receptor, and VEGFs and PGFs in mediating the vasodilatory actions of relaxin as published in preliminary reports. See text for further details.

Figure 3

Three-stage model of preeclampsia. See text for details.