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Ablation of leptin signaling disrupts the establishment, development, and maintenance of endometriosis-like lesions in a murine model.

ABSTRACT: Leptin, a 16-kDa cytokine, has been implicated in several reproductive processes and disorders. Notably, elevated leptin levels in the peritoneal fluid of women with mild endometriosis has been demonstrated, suggesting a role for this cytokine in the early stages of disease establishment. To gain insight into the functional significance of leptin during the initial requisite proliferative and neovascularization events involved in endometriosis, we investigated the effect of disruption of in vivo leptin signaling on the establishment and/or maintenance of an endometriosis-like lesion in a syngeneic immunocompetent mouse model of endometriosis. Findings of this study show that the disruption of leptin signaling by ip injection of the pegylated leptin peptide receptor antagonist (LPrA) impairs the establishment of endometriosis-like lesions (derived from uteri of C57BL/6 female siblings) and results in a reduction of viable organized glandular epithelium, vascular endothelial growth factor-A expression, and mitotic activity. LPrA treatment resulted in a significant reduction of microvascular density in endometriosis-like lesions after continuous and acute courses. Endometriosis-like lesions (derived from tissue with functional leptin receptor) of Lepr(db) hosts (nonfunctional leptin receptor) were phenotypically similar to those of LPrA-treated mice. Our results confirm that leptin signaling is a necessary component in lesion proliferation, early vascular recruitment, and maintenance of neoangiogenesis in a murine model of endometriosis.

SUBMITTER: Styer AK

PROVIDER: S-EPMC2219296 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Ablation of leptin signaling disrupts the establishment, development, and maintenance of endometriosis-like lesions in a murine model.

Styer Aaron K AK Sullivan Brian T BT Puder Mark M Arsenault Danielle D Petrozza John C JC Serikawa Takehiro T Chang Sung S Hasan Tayyaba T Gonzalez Ruben R RR Rueda Bo R BR

Endocrinology 20071025 2

Leptin, a 16-kDa cytokine, has been implicated in several reproductive processes and disorders. Notably, elevated leptin levels in the peritoneal fluid of women with mild endometriosis has been demonstrated, suggesting a role for this cytokine in the early stages of disease establishment. To gain insight into the functional significance of leptin during the initial requisite proliferative and neovascularization events involved in endometriosis, we investigated the effect of disruption of in vivo ...[more]

PMID: 17962343

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Project description:PurposeEndometriosis is a chronic condition characterized by high fibrotic content and affecting about 10% of women during their reproductive years. Yet, no clinically approved agents are available for non-invasive endometriosis detection. The purpose of this study was to investigate the utility of a gadolinium-based collagen type I targeting probe (EP-3533) to non-invasively detect endometriotic lesions using magnetic resonance imaging (MRI). Previously, this probe has been used for detection and staging of fibrotic lesions in the liver, lung, heart, and cancer. In this study we evaluate the potential of EP-3533 for detecting endometriosis in two murine models and compare it with a non-binding isomer (EP-3612).ProceduresFor imaging, we utilized two GFP-expressing murine models of endometriosis (suture model and injection model) injected intravenously with EP3533 or EP-33612. Mice were imaged before and after bolus injection of the probes. The dynamic signal enhancement of MR T1 FLASH images was analyzed, normalized, and quantified, and the relative location of lesions was validated through ex vivo fluorescence imaging. Subsequently, the harvested lesions were stained for collagen, and their gadolinium content was quantified by inductively coupled plasma optical emission spectrometry (ICP-OES).ResultsWe showed that EP-3533 probe increased the signal intensity in T1-weighted images of endometriotic lesions in both models of endometriosis. Such enhancement was not detected in the muscles of the same groups or in endometriotic lesions of mice injected with EP-3612 probe. Consequentially, control tissues had significantly lower gadolinium content, compared to the lesions in experimental groups. Probe accumulation was similar in endometriotic lesions of either model.ConclusionsThis study provides evidence for feasibility of targeting collagen type I in the endometriotic lesions using EP3533 probe. Our future work includes investigation of the utility of this probe for therapeutic delivery in endometriosis to inhibit signaling pathways that cause the disease.

Dataset Information

Ablation of leptin signaling disrupts the establishment, development, and maintenance of endometriosis-like lesions in a murine model.

Publications

Ablation of leptin signaling disrupts the establishment, development, and maintenance of endometriosis-like lesions in a murine model.

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