Relaxin-2 (Serelaxin): The Vasodilatory Peptide Hormone Driving Cardiovascular, Anti-Fibrotic, and Reproductive Research (2026)

# Relaxin-2 (Serelaxin): The Vasodilatory Peptide Hormone Driving Cardiovascular, Anti-Fibrotic, and Reproductive Research (2026)

Introduction

Relaxin-2 is a two-chain peptide hormone with a research history spanning nearly a century — yet its biology remains the subject of intense contemporary investigation. Best known as the active circulating form of the relaxin family and the parent molecule behind serelaxin (recombinant human relaxin-2), it exerts pleiotropic effects across the cardiovascular system, reproductive tissue, and multiple fibrosis-susceptible organs. Its receptor, RXFP1, is a structurally unique leucine-rich repeat GPCR with mechanistic features found in no other human receptor, making the relaxin system an intellectually distinctive domain of peptide pharmacology.

This profile reviews relaxin-2 structure, receptor biology, cardiovascular research, anti-fibrotic mechanisms, reproductive applications, and the latest clinical-stage RXFP1 agonist development — for research use only.

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Discovery and Relaxin Family Overview

Relaxin was first identified in 1926 by Frederick Hisaw, who observed that serum from pregnant guinea pigs caused relaxation of the pubic symphysis in non-pregnant animals — naming the responsible substance for its tissue-relaxing effect. Decades of subsequent research identified relaxin as a peptide hormone structurally related to insulin, and eventually the human gene family was fully characterized.

The human relaxin family comprises seven peptides encoded by distinct genes:

Relaxin-2 is the primary pharmacologically active form in humans and the basis for serelaxin (recombinant human H2 relaxin), which entered clinical trials for acute heart failure. When researchers refer to "relaxin" in most cardiovascular or fibrosis literature, they mean relaxin-2 acting through RXFP1.

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Molecular Structure of Relaxin-2

Relaxin-2 shares the insulin superfamily's distinctive two-chain, three-disulfide architecture:

• •B chain: ~24 amino acids; contains the receptor-binding motif (RXXXRXXI), critical for RXFP1 engagement
• •A chain: ~24 amino acids; stabilizes the active conformation
• •Disulfide bonds: Two inter-chain disulfide bonds (A-B) and one intra-A-chain bond
• •Molecular weight: ~6,000 Da

The B-chain Arg-X-X-X-Arg-X-X-Ile (RXXXRXXI) motif is essential for high-affinity binding to RXFP1. Unlike insulin, whose A and B chains fold compactly together, relaxin presents a more extended conformation that accommodates the distinct topography of the RXFP1 extracellular leucine-rich repeat domain.

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RXFP1: A Structurally Unique GPCR

RXFP1 (Relaxin Family Peptide Receptor 1, formerly LGR7) is one of the most architecturally distinctive GPCRs in the human proteome. It belongs to the leucine-rich repeat (LRR) subfamily of GPCRs — a group that also includes the gonadotropin receptors (FSHR, LHCGR, TSHR) — but carries a unique N-terminal LDLa (low-density lipoprotein receptor class A) module found in no other human GPCR.

Structural organization of RXFP1:

1. LDLa module: N-terminal cysteine-rich domain essential for intramolecular signaling

2. 10 leucine-rich repeats (LRRs): Primary binding site for relaxin-2

3. Hinge region and transmembrane domain: Classic GPCR seven-helix architecture

4. Intracellular loops: G protein and β-arrestin coupling sites

Two-Stage Binding and Autoinhibition

RXFP1 activates through an unusual two-stage binding model:

1. Relaxin-2 first docks at the high-affinity LRR domain in the extracellular region

2. The peptide then makes a secondary interaction with a low-affinity site near the transmembrane helices, which triggers receptor activation

Recent structural work (2023, PMC10530065) revealed that RXFP1 signals through a mechanism of autoinhibition: the LDLa module normally restrains receptor activity, and relaxin binding releases this inhibitory constraint to permit G protein coupling. This autoinhibition model explains why non-peptide RXFP1 agonists have been so difficult to develop — mimicking the relief of LDLa-mediated restraint is mechanistically complex.

RXFP1 Signaling Pathways

RXFP1 is expressed broadly across tissues: heart, kidney, lung, liver, brain, skin, blood vessels, uterus, and cervix — consistent with relaxin's pleiotropic physiological roles.

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Cardiovascular Research

Vasodilation and Hemodynamic Effects

Relaxin-2 is a potent vasodilator. The primary mechanism involves RXFP1-mediated activation of endothelial nitric oxide synthase (eNOS), increasing local NO production and causing smooth muscle relaxation in arterioles and small arteries. Additional mechanisms include:

• •Vascular gelatinase upregulation: MMP-2 and MMP-9 activation increases vascular compliance by remodeling the extracellular matrix of vessel walls
• •Endothelin receptor downregulation: Relaxin attenuates vasoconstrictor responses by reducing endothelin-1 (ET-1) receptor expression
• •Anti-platelet effects: Relaxin reduces platelet aggregation in certain experimental contexts

This vasodilatory profile led to serelaxin's clinical development for acute decompensated heart failure (ADHF), where hemodynamic relief is a therapeutic priority.

Serelaxin and the RELAX-AHF Clinical Program

RELAX-AHF (Phase IIb/III, ~1160 patients): The initial Phase IIb/III trial (published Lancet, 2013) showed that a 48-hour intravenous serelaxin infusion significantly relieved dyspnea, reduced 180-day cardiovascular mortality, and improved biomarker profiles in ADHF patients. This result generated substantial scientific excitement.

RELAX-AHF-2 (Phase III, ~6600 patients): The larger confirmatory Phase III trial failed to replicate the mortality benefit, with serelaxin not demonstrating statistically significant reduction in 180-day cardiovascular death. The trial was considered negative for the primary endpoint. Post-hoc analyses suggested potential benefit in subpopulations, and methodological debates continue in the heart failure research community.

The RELAX-AHF-2 failure is widely attributed to:

1. Serelaxin's very short half-life (<5 hours) limiting sustained receptor engagement

2. Heterogeneity of the ADHF population

3. Possible disconnect between short-term hemodynamic relief and long-term outcomes

This failure has redirected research toward long-acting RXFP1 agonists (see below).

Anti-Hypertrophic and Anti-Remodeling Effects

Beyond acute hemodynamics, relaxin-2 demonstrates anti-cardiac-remodeling properties in preclinical models:

• •Attenuates left ventricular hypertrophy in pressure-overload models
• •Reduces cardiomyocyte apoptosis
• •Inhibits cardiac fibrosis (see anti-fibrotic section)
• •Improves diastolic function in hypertensive rodent models

These properties support continued research into relaxin signaling in chronic heart failure models, even after the serelaxin ADHF setback.

AZD3427: Next-Generation RXFP1 Agonist

AZD3427, a synthetic single-chain RXFP1 peptide agonist with improved stability over native relaxin-2, completed a Phase 1a/b first-in-human study published in the Journal of the American Heart Association (2024). The Phase 1 trial demonstrated favorable safety and pharmacokinetic profile in healthy volunteers, with RXFP1-mediated hemodynamic effects consistent with RXFP1 activation. AZD3427 represents the next generation of RXFP1-targeting research compounds designed to overcome the half-life limitation of serelaxin.

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Anti-Fibrotic Research

Fibrosis research is arguably the area of greatest current activity for RXFP1-targeted compounds. Relaxin-2 has demonstrated anti-fibrotic effects in models of nearly every major organ system that undergoes pathological fibrosis.

Mechanisms of Anti-Fibrotic Action

Relaxin-2 disrupts fibrosis at multiple nodes of the fibrogenic cascade:

1. TGF-β/SMAD inhibition: Relaxin attenuates TGFβ-pSMAD2/3 signaling — the master driver of myofibroblast activation and collagen synthesis — through RXFP1-mediated cAMP and eNOS/NO pathways

2. MMP upregulation: Increases matrix metalloproteinase (MMP-1, MMP-2, MMP-9, MMP-13) expression, promoting collagen degradation

3. TIMP downregulation: Reduces tissue inhibitors of metalloproteinases, tilting the MMP/TIMP balance toward collagenolysis

4. Myofibroblast deactivation: Inhibits the transition of fibroblasts and stellate cells to the activated, contractile, collagen-secreting myofibroblast phenotype

5. EndMT inhibition: Serelaxin inhibits endothelial-to-mesenchymal transition (EndMT) via endothelial RXFP1, reducing the conversion of endothelial cells to fibroblast-like cells — a key mechanism in cardiac fibrosis (PMID: 32226528)

Liver Fibrosis

Hepatic stellate cells (HSCs) upregulate RXFP1 when activated by fibrogenic stimuli, creating a targetable feedback loop. Relaxin treatment in experimental liver fibrosis models reduces:

• •Collagen I and III deposition
• •α-SMA (myofibroblast marker) expression
• •Portal hypertension indices
• •HSC activation markers

Recent 2025 research using circular RNA-encoded relaxin-2 (PMC12805276) demonstrated reversal of liver fibrosis biomarkers in experimental models, establishing a gene therapy approach to sustained RXFP1 activation for hepatic fibrosis research.

Renal Fibrosis

RXFP1 is expressed in kidney tubular epithelial cells, glomeruli, and interstitium. In preclinical CKD models, relaxin treatment reduces tubulointerstitial fibrosis, glomerulosclerosis, and inflammatory infiltration. The combination of anti-fibrotic and vasodilatory actions is particularly relevant for renal research, where fibrosis and microvascular dysfunction co-evolve.

Pulmonary Fibrosis

In silica-induced pulmonary fibrosis models, relaxin reduces collagen type I accumulation and increases MMP-2 expression. The therapeutic window for relaxin in pulmonary fibrosis research remains an active area, particularly as RXFP1 expression is documented in lung fibroblasts and alveolar macrophages.

Long-Acting RXFP1 Agonists for Chronic Fibrosis Research

Given that chronic fibrosis demands sustained receptor engagement (unlike acute heart failure requiring only 48-hour infusion), significant engineering effort has gone into extending relaxin-2 half-life:

• •Fc-fusion relaxins: Fc-relaxin-2 fusions generate half-lives of 3–5 days in mice (PMC11372834)
• •Protein-in-Protein (PiP) technology: Inserting a single-chain relaxin construct into the CDR of an IgG backbone (PMC12884953)
• •Single-chain peptide agonists: Truncated, cyclized, or stapled relaxin analogs with protease resistance

These platforms provide research tools for investigating chronic fibrosis regression in experimental models without continuous infusion requirements.

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Reproductive Biology Research

Relaxin-2's classical role is reproductive. During pregnancy, relaxin-2 is secreted by the corpus luteum of the ovary and (in humans) the decidua and placenta, with peak circulating levels in the first trimester.

Cervical Remodeling

Relaxin promotes remodeling of the cervical extracellular matrix via:

• •MMP-1 and MMP-3 upregulation
• •Collagen fibril reorganization
• •Increased water content (hydration of glycosaminoglycans)
• •Reduction of cross-linking in collagen fibrils

Clinical trials investigating intravaginal recombinant relaxin for cervical ripening showed modest effects but have not established a role in obstetric interventions. The basic science of relaxin in cervical biology nevertheless provides a model for understanding hormone-driven ECM remodeling.

Decidualization

Relaxin stimulates endometrial decidualization — the structural transformation of the endometrium preparing for implantation. Mechanisms include:

• •Stimulation of decidual cell differentiation
• •Regulation of local MMP activity (context-dependent: inhibits some MMPs in endometrium while activating them in other tissues)
• •Promotion of angiogenesis in the developing decidua
• •Modulation of local immune cell (uterine NK cell) populations

INSL3 and RXFP2 in Reproductive Research

The closely related peptide INSL3 (Insulin-Like Peptide 3), secreted by testicular Leydig cells and ovarian theca cells, acts through RXFP2 to regulate reproductive organ development and steroidogenesis. RXFP2 is essential for gubernaculum development and testicular descent — INSL3/RXFP2 knockout models display cryptorchidism. In adult biology, INSL3 serves as a Leydig cell functional marker and modulates follicular androgen production. The INSL3/RXFP2 system represents a distinct but related research area within the relaxin peptide family.

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Relaxin-3 and CNS Research

Relaxin-3 (H3) deserves mention as the most recently discovered and most divergent relaxin family member, expressed predominantly in the nucleus incertus (NI) of the brainstem. Relaxin-3 signals through:

• •RXFP3 (primary receptor, brain-enriched)
• •RXFP1 (secondary; relaxin-2 also activates RXFP1 but not RXFP3)

Relaxin-3/RXFP3 research has implicated this system in:

• •Stress responses and CRF interaction
• •Feeding behavior and appetite modulation
• •Arousal and sleep-wake regulation
• •Hippocampal function and memory consolidation

Targeting the relaxin-3/RXFP3 system has been reviewed as a potential approach for anxiety, metabolic dysregulation, and cognitive research tools (PMC11027024). This CNS-focused biology is distinct from the cardiovascular/fibrotic profile of relaxin-2/RXFP1.

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Research Tools

RXFP1 Agonists

RXFP1 Antagonists

RXFP3-Selective Tools

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Research Applications Summary

1. Cardiovascular fibrosis models: RXFP1 agonism for cardiac anti-remodeling and anti-hypertrophic research

2. Hepatic fibrosis: Stellate cell activation, collagen remodeling, portal hypertension models

3. Renal and pulmonary fibrosis: RXFP1-expressing resident fibroblast and macrophage biology

4. Vasodilation/hemodynamics: eNOS-dependent NO pathway research; endothelial function

5. Reproductive ECM remodeling: Cervical, uterine, and mammary gland models

6. Endometrial biology: Decidualization, implantation models

7. INSL3/RXFP2: Leydig cell function, steroidogenesis, testicular descent models

8. Relaxin-3/RXFP3: CNS stress, appetite, and memory circuit research

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Research Notes

All content in this profile relates to Research Use Only (RUO) applications. Relaxin-2, serelaxin, and related RXFP1 ligands are investigational peptide compounds used exclusively in preclinical and laboratory research. Nothing here constitutes medical or clinical advice, dosing guidance, or protocols for human or animal administration.

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Author: Peptides.SO Research Team | Category: Peptide Guides | 2026

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Relaxin in Connective Tissue and Musculoskeletal Research

Relaxin's historical identification as a "relaxin" agent was based on its effects on connective tissue, and this remains a vibrant research area beyond major organ fibrosis.

Ligament and Tendon Biology

RXFP1 is expressed in fibroblasts of ligamentous tissue, and relaxin alters ligament mechanical properties by:

• •Increasing MMP-mediated collagen turnover in fibroblast populations
• •Reducing cross-link density in collagen fibril networks
• •Modifying proteoglycan composition of connective tissue ECM

Research has documented relaxin's role in ligament laxity, including increased joint laxity during pregnancy when relaxin levels are elevated. This has implications for musculoskeletal research models examining hormone-dependent connective tissue remodeling, ligament healing, and rehabilitation biology.

A 2023 review (PMC10134402) comprehensively examined relaxin's regulatory role in fibrotic ligament diseases, including Dupuytren's contracture, where pro-fibrotic ECM accumulation in palmar fascia leads to progressive finger contracture — an area where RXFP1 agonism has been proposed as a research target.

Wound Healing and Dermal Research

The skin expresses RXFP1, and relaxin has demonstrated effects on dermal fibroblast biology:

• •Reduces scar tissue formation in wound healing models
• •Attenuates post-traumatic dermal fibrosis
• •Relaxes pre-contracted skin equivalent constructs in vitro

These effects parallel the anti-fibrotic mechanisms in visceral organs but occur in dermal fibroblasts — providing a tissue culture model accessible for mechanistic dissection of RXFP1 signaling.

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Metabolic and Kidney Research Depth

Renal Hemodynamics

Beyond anti-fibrotic effects, relaxin-2 exerts direct renal hemodynamic actions relevant to metabolic syndrome and CKD research:

• •Increases glomerular filtration rate (GFR) through afferent arteriolar vasodilation
• •Promotes renal vasodilation via gelatinase-dependent MMP activation in the renal vasculature
• •Reduces renal vascular resistance
• •Attenuates salt-dependent hypertension in rodent models (DOCA-salt model)

The combination of renal vasodilation and anti-fibrotic effects positions RXFP1 agonism as a mechanistically interesting target for chronic kidney disease research, particularly in models combining hemodynamic compromise with progressive interstitial fibrosis.

Cardiorenal Research Models

The cardiovascular effects review (PMC11269324) synthesizes data showing that relaxin-2 exerts coordinated cardiorenal protective effects through:

1. Reducing cardiac preload and afterload via vasodilation

2. Improving renal function through GFR preservation

3. Attenuating both cardiac and renal fibrosis through shared RXFP1-mediated anti-fibrotic pathways

4. Suppressing neurohormonal activation (RAAS, sympathetic) that drives cardiorenal syndrome

This multi-organ coordination makes relaxin-2 research particularly valuable for integrated cardiorenal model studies rather than isolated organ preparations.

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Receptor Selectivity and the Relaxin Peptide Design Challenge

Developing RXFP1-selective research tools presents unique challenges:

Why RXFP1 is hard to drug with small molecules:

• •The two-stage binding mechanism (LRR domain + transmembrane) requires simultaneous engagement of two distinct sites
• •The LDLa autoinhibition mechanism means relieving intramolecular restraint, not simply occupying a classical orthosteric pocket
• •Non-peptide molecules have generally shown partial agonism, antagonism, or allosteric modulation rather than full agonism

Recent progress:

• •Small molecule RXFP1 agonists have been identified through HTS campaigns but retain potency limitations compared to the native peptide
• •Biased RXFP1 agonists that selectively activate cAMP over β-arrestin (or vice versa) represent an emerging strategy for mechanistic dissection
• •Stapled peptide relaxin analogs that maintain helical structure and improve protease resistance are under research characterization

The RXFP2 receptor (INSL3 primary receptor) has also seen recent small molecule agonist discovery, reported in Communications Biology (2022), providing the first selective tool compounds for RXFP2-specific biology — separating INSL3/RXFP2 research from the relaxin-2/RXFP1 system pharmacologically.