Characteristics of Multi-Organ Lymphangiectasia Resulting from Temporal Deletion of Calcitonin Receptor-Like Receptor in Adult Mice

Samantha L Hoopes,Kathleen M Caron,Helen H Willcockson,Partha Mukhopadhyay

doi:10.1371/journal.pone.0045261

Samantha L Hoopes, Kathleen M Caron + Show 2 more

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https://doi.org/10.1371/journal.pone.0045261

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Journal: PloS one	Publication Date: Sep 17, 2012
Citations: 45	License type: CC BY 4.0

Affiliation: University of North Carolina at Chapel Hill

Abstract

Adrenomedullin (AM) and its receptor complexes, calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2/3, are highly expressed in lymphatic endothelial cells and are required for embryonic lymphatic development. To determine the role of Calcrl in adulthood, we used an inducible Cre-loxP system to temporally and ubiquitously delete Calcrl in adult mice. Following tamoxifen injection, Calcrlfl/fl/CAGGCre-ER™ mice rapidly developed corneal edema and inflammation that was preceded by and persistently associated with dilated corneoscleral lymphatics. Lacteals and submucosal lymphatic capillaries of the intestine were also dilated, while mesenteric collecting lymphatics failed to properly transport chyle after an acute Western Diet, culminating in chronic failure of Calcrlfl/fl/CAGGCre-ER™ mice to gain weight. Dermal lymphatic capillaries were also dilated and chronic edema challenge confirmed significant and prolonged dermal lymphatic insufficiency. In vivo and in vitro imaging of lymphatics with either genetic or pharmacologic inhibition of AM signaling revealed markedly disorganized lymphatic junctional proteins ZO-1 and VE-cadherin. The maintenance of AM signaling during adulthood is required for preserving normal lymphatic permeability and function. Collectively, these studies reveal a spectrum of lymphatic defects in adult Calcrlfl/fl/CAGGCre-ER™ mice that closely recapitulate the clinical symptoms of patients with corneal, intestinal and peripheral lymphangiectasia.

Highlights

The lymphatic vascular system is a complex vascular network that permeates nearly every organ of the body and plays a critical role in the maintenance of fluid homeostasis, the absorption of intestinal lipids and the trafficking and maturation of immune cells [1]
Vessels Tamoxifen injection resulted in a significant reduction of calcitonin receptor-like receptor (Calcrl) gene expression in Calcrlfl/fl/CAGGCre-ERTM animals compared to Calcrlfl/fl animals and to Calcrlfl/fl/CAGGCre-ERTM non-injected animals as indicated by qRT-PCR of lung and heart tissue (Figure S2)
We found no significant histological differences in the optic nerve of Calcrlfl/fl/CAGGCre-ERTM mice compared to Calcrlfl/fl control mice

Summary

Introduction

The lymphatic vascular system is a complex vascular network that permeates nearly every organ of the body and plays a critical role in the maintenance of fluid homeostasis, the absorption of intestinal lipids and the trafficking and maturation of immune cells [1]. The past dozen years has provided a relative explosion of new and sometimes unexpected genes involved in the development of the lymphatic vascular system, based largely on elegant and exciting embryonic phenotypes uncovered in gene knockout studies in mice and in vertebrate model organisms like zebrafish and xenopus [3]. Some of these discoveries have even paved the way toward the identification and better understanding of human genes in which mutations are causally associated with congenital, primary lymphedema such as FOXC2, FLT4, SOX18, GJC2 and CCBE1. Lymphangiectasia can be associated with a variety primary, congenital lymphedema syndromes, there is currently no known genetic pathway that directly and predominantly contributes to lymphangiectasia

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