Brief Review Unveiling the Vasodilatory Actions and Mechanisms of Relaxin

Relaxin is a 6-kDa peptide hormone that is secreted from the corpus luteum of the ovary and circulates in the blood during pregnancy in several species, including humans, rats, and mice1 (see Appendix for relaxin ligand and receptor nomenclature). Hisaw and colleagues,2,3 who discovered the hormone, provided the first evidence, albeit structural in nature, that the vasculature is a relaxin target. In ovariectomized monkeys administered relaxin, they noted marked morphological changes in the endothelial cells of endometrial blood vessels consistent with hypertrophy and hyperplasia, as well as enlargement of arterioles and capillaries.4,5 Functional evidence for a vasodilatory role of the hormone was initially reported by St-Louis and Massicotte,6 who demonstrated that chronic infusion of purified rat or porcine relaxin decreased systolic blood pressure in female spontaneously hypertensive rats but not Wistar-Kyoto rats. In another study, the same group of investigators showed that short-term administration of purified rat relaxin decreased mean arterial pressure in female spontaneously hypertensive rats as early as 8 hours after initiating the infusion, and the vasoconstrictor responses to norepinephrine and arginine vasopressin were blunted in the mesenteric circulation of these animals perfused in situ.7 Subsequently, some doubt about the physiological importance of the vascular role of relaxin was raised, when Ahokas et al8 found that the gestational decline in systolic blood pressure and decrease in vascular reactivity to angiotensin II were comparable in gravid spontaneously hypertensive rats with and without ovaries and, thus, with and without circulating relaxin. Further supportive evidence for vascular effects of relaxin was garnered by Bani-Sacchi et al,9 who reported that, in the Langendorff preparation, relaxin acutely increased coronary blood flow in rat and guinea pig hearts. This group also showed that the vasodilatory action of relaxin in the coronary circulation was prevented by N-monomethyl-L-arginine, an NO synthase (NOS) inhibitor.9 More recent understanding of relaxin as a vasodilatory hormone has stemmed, in part, from investigations of the maternal renal and cardiovascular adaptations to pregnancy, in which relaxin is emerging as an important player. The overall objective of this Brief Review is 2-fold: first, to highlight the vasodilatory actions of relaxin, particularly in the context of pregnancy; and, second, to outline current understanding of the mechanisms underlying the vasodilatory attributes of relaxin with emphasis on the role of arterial gelatinases.