Relaxin Therapy Reverses Large Artery Remodeling and Improves Arterial Compliance in Senescent Spontaneously Hypertensive Rats

Abstract

Abstract-Hypertension and aging are associated with large artery structural remodeling and stiffening, which are known to increase cardiovascular risk. Relaxin is a peptide hormone with potent antifibrotic action in multiple organs. Although relaxin is able to reduce peripheral vascular resistance and improve arterial compliance in rats, it remains unclear whether the improvement in compliance is indirectly attributed to a vasodilatory action or whether relaxin is able to reverse arterial remodeling and stiffening directly in aged hypertensive animals. Senescent spontaneously hypertensive rats (17 months old) were treated with relaxin for 2 weeks (0.5 mg/kg per day) followed by a 1-week washout period.We determined large artery compliance using in vivo and in vitro techniques and quantified arterial remodeling by morphological and chemical means. Relaxin therapy significantly reversed aortic remodeling (ie, increases in vessel size, wall thickness, and collagen content) and improved arterial compliance, effects independent of its vasodilatory action. In relaxin-treated spontaneously hypertensive rats, arterial collagen content showed a greater reduction (Ϫ31%; PϽ0.05) than that of elastin (Ϫ8%) 4 Several studies have provided strong evidence for relaxin as a potent vasodilator in vitro and in vivo. [5][6][7] The signaling mechanisms involve stimulating nitric oxidase synthases or endothelin-␤-mediated vasodilatory signaling 8 and antagonizing vasoconstriction induced by angiotensin II, endothelin 1, and catecholamines. 9 Conrad and colleagues 7,10 showed that treatment with relaxin either acutely or for a period of 10 days increased large artery compliance and cardiac output without a change in blood pressure in normotensive or hypertensive rats.Another unique feature of relaxin is its potent antifibrotic action. 11,12 In relaxin knockout mice, fibrosis occurs with aging in multiple organs. 11,[13][14][15] Conversely, administration of relaxin for 2 weeks effectively reversed organ fibrosis in relaxin knockout mice or other models of cardiac fibrosis, 11 including spontaneously hypertensive rats (SHR) showing reduced cardiac and renal fibrosis by relaxin therapy for 2 weeks. 16 Relaxin achieves its antifibrotic action through multiple mechanisms involving suppression of collagen synthesis via inhibiting fibroblast activation/proliferation and promotion of collagen degradation through activating matrix metalloproteinases. 11 Previous studies on the cardiovascular properties of relaxin have focused on its antifibrotic actions in the heart or blood pressure-lowering effect, 2,7 and it remains unknown whether chronic relaxin treatment in hypertensive models is able to reverse remodeling of large arteries. Progress in this area would advance our understanding of the therapeutic potential of relaxin. In the current study, we have addressed the hypothesis that relaxin therapy in SHRs is able to reverse large artery remodeling with accompanied improvement in arterial compliance. To make our findings more applicab...

Relaxin regulates vascular wall remodeling and passive mechanical properties in mice

“…Furthermore, administration of rhRLX to older RLX Ϫ/Ϫ mice significantly reversed the established fibrosis in lungs, kidneys, and heart (36). Xu et al (52) recently reported comparable results in relaxin-treated senescent spontaneously hypertensive rats, i.e., the hormone increased SMC density and reduced collagen in the aorta.…”

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

“…However, in patients not receiving angiotensin converting enzyme inhibitors, inhibition of cyclooxygenase had little effect on the vasodilator response to relaxin (Fisher et al, 2002). The vasodilator mechanisms suggested for relaxin in both humans and in animal models involve activation of NOS (Nistri and Bani, 2003;, VEGF, placental growth factor (PGF), matrix metalloproteinases, ET B receptors (Novak et al, 2002;Dschietzig et al, 2003), and modification of the extracellular matrix of the vessel walls (Jeyabalan et al, 2003;Lekgabe et al, 2005;Xu et al, 2010;McGuane et al, 2011b). These responses have a distinct temporal hierarchy.…”

Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin)

“…Along this line of thought, RLX was shown to improve the grafting and antifibrotic efficacy of stem cell therapy for organ repair in various in vivo models (Formigli et al, 2007;Bonacchi et al, 2009;Huuskes et al, 2015). The possibility that RLX may be therapeutically effective in COPD is further supported by the results of an experimental in vivo study on age-related vascular damage, which have shown that RLX treatment possesses the unique ability to not only prevent but also revert established arterial remodeling and fibrosis (Xu et al, 2010).…”