Maternal vasodilation in pregnancy: the emerging role of relaxin

Abstract

Pregnancy is a unique physiological condition of profound maternal renal and systemic vasodilation. Our goal has been to unveil the reproductive hormones mediating this remarkable vasodilatory state and the underlying molecular mechanisms. In addition to advancing our knowledge of pregnancy physiology, reaching this goal may translate into therapeutics for pregnancy pathologies such as preeclampsia and for diseases associated with vasoconstriction and arterial stiffness in nonpregnant women and men. An emerging player is the 6 kDa corpus luteal hormone relaxin, which circulates during pregnancy. Relaxin administration to rats and humans induces systemic and renal vasodilation regardless of sex, thus mimicking the pregnant condition. Immunoneutralization or elimination of the source of circulating relaxin prevents renal and systemic vasodilation in midterm pregnant rats. Infertile women who become pregnant by donor eggs (IVF with embryo transfer) lack a corpus luteum and circulating relaxin, and they show a markedly subdued gestational increase in glomerular filtration rate. These data implicate relaxin as one of the vasodilatory reproductive hormones of pregnancy. There are different molecular mechanisms underlying the so-called rapid and sustained vasodilatory actions of relaxin. The former is mediated by Gα(i/o) protein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase, the latter by vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. The gelatinases, in turn, hydrolyze big endothelin (ET) at a gly-leu bond to form ET(1-32), which activates the endothelial ET(B) receptor/nitric oxide vasodilatory pathway.

Fig. 1.

Regulation of cardiac output during pregnancy. In this theoretical model, profound maternal vasodilation (decreased ventricular afterload) in the first trimester initiates a large increase in cardiac output and relative arterial underfilling, the latter activating mechanisms that lead to volume retention (increased preload), thereby abetting the increase in cardiac output. See text for details and supporting references. [Modified from Gilson GJ, Mosher MD, Conrad KP (40)].

Fig. 2.

Relaxin administration mimics the renal and systemic vasodilation of pregnancy. ?, not tested; +/−, chronic, but not acute relaxin administration increased GFR in humans. See text for details and supporting references.

Fig. 3.

Working model of relaxin sustained-vasodilatory response. The precise localization of VEGF and PGF in the relaxin vasodilatory pathway is currently unknown, but two possibilities are depicted (?): relaxin may increase expression of angiogenic growth factor(s) in the arterial wall and/or release them from the extracellular matrix via MMP-9 or -2. Inhibitors of pregnancy- and/or relaxin-induced vasodilation are shown in the boxes. ET, endothelin; MMP, matrix metalloproteinase; ECM, extracellular matrix; RPF, renal plasma flow; GFR, glomerular filtration rate; RXFP, relaxin/insulin-like family peptide receptors; SU5416, vascular endothelial growth factor receptor tyrosine kinase inhibitor; GM6001, a general MMP inhibitor; cyclic CTT, a specific peptide inhibitor of MMP-2, cyclic CTTHWGFTLC; TIMP-2, tissue inhibitor of metalloproteinase; RES-701–1, a specific ET_B receptor antagonist; SB209670, a mixed ET_A and ET_B receptor antagonist; l-NAME, N^G-nitro-l-arginine methyl ester; l-NMMA, l-N^G-monoethyl-arginine. Note that RXFP2 knockout (in mice), STT (control peptide for cyclic CTT), heat inactivated TIMP-2, BQ-123 (a specific ET_A receptor antagonist), phosphoramidon (an inhibitor of the classical endothelin converting enzyme), d-NAME, and isotype-matched IgGs (controls for neutralizing antibodies) did not affect the sustained vasodilatory responses to relaxin. See text for details and supporting references. [Modified from McGuane JT, Danielson LA, Debrah JE, Rubin JP, Novak J, Conrad KP (51)].

Fig. 4.

Working model of rapid stimulation of nitric oxide (NO) production by relaxin in endothelial cells. Relaxin activates RXFP1, leading to Gα_i3 activation and dissociation of the corresponding βγ-subunits (blocked by PTX), which in turn activates the class 1B phosphatidylinositol 3-kinase-γ (PI3Kγ). PI3Kγ phosphorylates phosphatidylinositol lipids in inner leaflet of the cell membrane (not shown; blocked by LY294002 and wortmannin), which ultimately promotes phosphorylation of Akt (blocked by MK-2206) and endothelia NO synthase (eNOS), leading to NO generation (blocked by l-NAME/l-NMMA). This pathway shares common downstream effector components with the VEGF pathway, which could explain the potentiation of rapid relaxin-induced vasodilation in the presence of SU5416. See text for details and supporting references. [Modified from McGuane JT, Debrah JE, Sautina L, Rubin JP, Novak J, Segal MS, Conrad KP (52).]