Effects of Relaxin on Arterial Dilation, Remodeling, and Mechanical Properties

Abstract

Administering relaxin to conscious rats and humans elicits systemic and renal vasodilation. The molecular mechanisms vary according to the duration of relaxin exposure-so-called "rapid" (within minutes) or "sustained" (hours to days) vasodilatory responses-both being endothelium-dependent. Rapid responses are mediated by G(αi/o) protein coupling to phosphoinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of nitric oxide synthase. Sustained responses are mediated by vascular endothelial and placental growth factors, as well as increases in arterial gelatinase activity. Thus, after hours or days of relaxin treatment, respectively, arterial MMP-9 or MMP-2 hydrolyze "big" endothelin (ET) at a gly-leu bond to form ET(1-32), which in turn activates the endothelial ET(B) receptor/nitric oxide vasodilatory pathway. Administration of relaxin to conscious rats also increases global systemic arterial compliance and passive compliance of select isolated blood vessels such as small renal arteries (SRA). The increase in SRA passive compliance is mediated by both geometric remodeling (outward) and compositional remodeling (decreased collagen). Relaxin-induced geometric remodeling has also been observed in brain parenchymal arteries, and this remodeling appears to be via the activation of peroxisome proliferator-activated receptor-γ. Given the vasodilatory and arterial remodeling properties of relaxin, the hormone may have therapeutic potential in the settings of abnormal pregnancies, heart failure, and pathologies associated with stiffening of arteries.

Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats

“…In regards to the cardiovascular system, in both male and female humans and rats, chronic administration of RLX causes vascular remodeling, angiogenesis, and systemic vasodilation (8). Endogenous RLX is a major contributor to peripheral vasodilation and augmented renal function seen in pregnancy, and recent clinical trials suggest that exogenously administered RLX may have therapeutic value in treating heart-failure patients (2,8,14).In addition to peripheral vascular effects, circulating RLX plays an important role in the central nervous system (CNS) regulation of fluid and electrolyte balance during pregnancy via activation of projection neurons originating in forebrain circumventricular organs. In the first half of pregnancy, RLX, through an ANG II-dependent mechanism in the subfornical organ (SFO), plays a critical role in central resetting of arginine-vasopressin (AVP) secretion, contributing to the expanded plasma volume in pregnancy (18,28,34,39).…”

“…In regards to the cardiovascular system, in both male and female humans and rats, chronic administration of RLX causes vascular remodeling, angiogenesis, and systemic vasodilation (8). Endogenous RLX is a major contributor to peripheral vasodilation and augmented renal function seen in pregnancy, and recent clinical trials suggest that exogenously administered RLX may have therapeutic value in treating heart-failure patients (2,8,14).…”

“…Although best known for its role in growth and remodeling of the female reproductive tract during pregnancy, RLX peptide and RLX binding sites are present in male reproductive tissue and the heart, vasculature, kidney, and brain of both males and females. In regards to the cardiovascular system, in both male and female humans and rats, chronic administration of RLX causes vascular remodeling, angiogenesis, and systemic vasodilation (8). Endogenous RLX is a major contributor to peripheral vasodilation and augmented renal function seen in pregnancy, and recent clinical trials suggest that exogenously administered RLX may have therapeutic value in treating heart-failure patients (2,8,14).…”

Therapeutic Effects of Serelaxin in Acute Heart Failure

“…The in-hospital and 30-day mortality rates modeling and passive mechanical properties. 12,17, 18 The ability of serelaxin to benefit patients with AHF by inducing similar changes was recently evaluated in phase-II and phase-III clinical trials. 9,11,19 A safety and tolerability phase-I trial assessed the effects of sequential dose levels of serelaxin in 16 patients with chronic HF, 7,11 and demonstrated that serelaxin (10-960μg · kg -1 · day -1 IV for 24 h) was well-tolerated, produced hemodynamic effects consistent with vasodilation and improved markers of renal function without adverse consequences.…”

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

“…Relaxin was shown to promote vasodilation, cardioprotection, antifibrotic wound healing, and angiogenesis (Brecht et al ., 2011; Conrad and Shroff, 2011; Du et al ., 2010). In various tumors, the RLN2‐RXFP1 has emerged as an important ligand–receptor system involved in controlling growth, migration/tissue invasion, angiogenesis, and metastasis (Klonisch et al ., 2007).…”