Vascular actions of relaxin: nitric oxide and beyond

Abstract

The peptide hormone relaxin regulates the essential maternal haemodynamic adaptations in early pregnancy through direct actions on the renal and systemic vasculature. These vascular actions of relaxin occur mainly through endothelium-derived NO-mediated vasodilator pathways and improvements in arterial compliance in small resistance-size arteries. This work catalysed a plethora of studies which revealed quite heterogeneous responses across the different regions of the vasculature, and also uncovered NO-independent mechanisms of relaxin action. In this review, we first describe the role of endogenous relaxin in maintaining normal vascular function, largely referring to work in pregnant and male relaxin-deficient animals. We then discuss the diversity of mechanisms mediating relaxin action in different vascular beds, including the involvement of prostanoids, VEGF, endothelium-derived hyperpolarisation and antioxidant activity in addition to the classic NO-mediated vasodilatory pathway. We conclude the review with current perspectives on the vascular remodelling capabilities of relaxin.

Linked articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

Figure 1

Effects of relaxin treatment in small renal arteries. Relaxin administration for hours and days increases MMP activities in ECs, leading to the conversion of big ET to ET_1–32, which activates endothelial ET_B receptors. Stimulation of endothelial ET_B receptors causes NO production and activates smooth muscle soluble guanylate cyclase, leading to cGMP accumulation and vasodilation. Vasodilation of small renal arteries reduces myogenic reactivity and renal vascular resistance (RVR) and increases renal blood flow (RBF) and GFR. Relaxin also directly acts on endothelial RXFP1 receptors to increase PI3 kinase‐dependent Akt‐eNOS phosphorylation, resulting in NO production. In addition to vasodilation, relaxin treatment causes vascular remodelling in the small renal arteries. Relaxin treatment increases angiogenic factors such as VEGF and PlGF, and reduces collagen content, causing vascular remodelling and increases arterial compliance. SVR, systemic vascular resistance.

Figure 2

Proposed mechanism(s) of acute i.v. injection of relaxin in rat mesenteric arteries. Relaxin injection causes rapid (3 h) and sustained (24 h) augmentation of BK‐evoked relaxation. The enhanced BK‐mediated relaxation is dependent on the IK_Ca channels 3 h after acute i.v. relaxin injection. In contrast, the sustained (24 h) relaxation to BK is dependent on PGI₂.