From pregnancy to cardiovascular disease: Lessons from relaxin‐deficient animals to understand relaxin actions in the vascular system

Abstract

Early maternal vascular adaptations to pregnancy are predominantly driven by changes in vascular tone, reactivity, and remodeling. Failure of the maternal systemic vasculature to adapt sufficiently can lead to serious complications of pregnancy. The hormone relaxin is widely recognized for its contribution to the essential renal and systemic hemodynamic adaptations in early pregnancy through direct actions on the maternal vasculature. Studies in relaxin gene knockout mice revealed that endogenous relaxin is not only a "pregnancy hormone" but has pleiotropic actions in various tissues in males and non-pregnant females. There is strong interest in relaxin's actions in the vasculature and its utility in the treatment of vascular diseases. Relaxin treatment in rodents for 2-5 days or acute intravenous injection enhances endothelium-dependent relaxation and decreases myogenic tone in resistance arteries. These vascular actions are prolonged, even in the absence of circulating relaxin, and are underpinned by the production of endothelium-derived relaxing factors including nitric oxide, endothelium-derived hyperpolarization, and prostacyclin. Relaxin is also capable of remodeling the vascular wall in a variety of blood vessels in disease conditions. Lessons learned in pregnancy research have aided studies investigating the potential therapeutic potential of relaxin in cardiovascular disease.

Relaxin Attenuates Organ Fibrosis via an Angiotensin Type 2 Receptor Mechanism in Aged Hypertensive Female Rats

“…[40][41][42][43][44] In the kidney RLX is a potent vasodilator dependent on a functional NO synthase-NO system. 45 Mechanistically, RLX dilates both the afferent and efferent arterioles, causing a significant increase in renal blood flow and a marked increase in GFR and urine flow. 40,43,44 In addition, RLX has direct effects on the renal tubules, possibily via an AT 2 R-bradykininnitric oxide (NO)-cGMP mechanism, 46,47 to inhibit sodium reabsorption, 40 which may also contribute to an increase in urine flow.…”

Hypertension in Women

“…Many of the hemodynamic adaptations during pregnancy may be assigned to relaxin. This polypeptide is synthetized by corpus luteum and it is mainly responsible for vascular remodeling and vasodilatation, which is predominantly achieved by the stimulation of NO system and alteration in the expression of endothelin ET 1B receptors (67). Beside aforementioned hemodynamic changes, pregnancy is also characterized by the increase in renal blood flow, glomerular filtration rate, activity of the renin angiotensin aldosterone system and enhanced activity of the sympathetic nervous system.…”

The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice

“…Furthermore, it was demonstrated that Cmpd17b administered during reperfusion in vivo reduces cardiac necrosis, inflammation, cardiac remodelling, and improves cardiac function [15]. Endothelial cells release several vasoactive factors that regulate the tone of the underlying smooth muscles cells [16][17][18]. The impact of FPR agonists on the regulation of vascular tone under physiological condition remains unclear and contradicting.…”