ArticleCirculation research2018
Mechanisms of Connexin-Related Lymphedema.
Article in Circulation research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 82 citations in OpenAlex.
- GLP-1 Receptors Are Enriched in the Lymphatic Endothelium and Their Pharmacological Activation With Semaglutide Improves the Pumping Capacity of Lymphatic Vessels.Microcirculation (New York, N.Y. : 1994) · 2026Article
- Pacemaking in the lymphatic system.The Journal of physiology · 2026Review
- Guidelines for evaluating endothelial function in vascular tissue.American journal of physiology. Heart and circulatory physiology · 2026Review
- Novel GJC2 and OBSCN variants co-segregating in a Chinese primary lymphedema pedigree.Orphanet journal of rare diseases · 2026Article
- Development and validation of an interpretable stacking-based risk model for breast cancer- related lymphoedema: a cross-sectional study.Frontiers in oncology · 2026Article
- Article
- Regulation of Collecting Lymphatic Vessel Contractile Function by TRPV4 Channels.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Integrated single-cell sequencing for the development of a GJA4-based precision immuno-prognostic model in melanoma.Translational oncology · 2025Article
- Single-Cell Transcriptomics and Lineage Tracing Unveil Parallels in Lymphatic Muscle and Venous Smooth Muscle Development, Identity, and Function.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Control of lymphatic pacemaking and pumping by mechanobiological signals.The Journal of physiology · 2025Article
- Clinical Relevance of Animal Models of Lymphatic Dysfunction and Lymphedema.Microcirculation (New York, N.Y. : 1994) · 2025Review
- Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice.Developmental cell · 2025Article
- Characteristics and advances in signaling pathways, cellular communication, cell junctions, and oxidative stress in lymphedema.Frontiers in cell and developmental biology · 2025Review
- Advances in etiology, pathophysiology, diagnosis, and management of lymphedema: a comprehensive review.Frontiers in medicine · 2025Review
- Chronic metabolic stress impairs lymphatic contractility via activation of KATP channels in a mouse model of Type-2 diabetes.Frontiers in physiology · 2025Article
- Overview of Lymphatic Muscle Cells in Development, Physiology, and Disease.Microcirculation (New York, N.Y. : 1994) · 2024Review
- Acute Metabolic Stress Induces Lymphatic Dysfunction Through KATP Channel Activation.Function (Oxford, England) · 2024Article
- The Lymphatic Vascular System: Does Nonuniform Lymphangion Length Limit Flow-Rate?Journal of biomechanical engineering · 2024Article
- Connexin-45 is expressed in mouse lymphatic endothelium and required for lymphatic valve function.JCI insight · 2024Article
- Loss of anoctamin 1 reveals a subtle role for BK channels in lymphatic muscle action potentials.The Journal of physiology · 2024Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
rationaleMutations in GJC2 and GJA1, encoding Cxs (connexins) 47 and 43, respectively, are linked to lymphedema, but the underlying mechanisms are unknown. Because efficient lymph transport relies on the coordinated contractions of lymphatic muscle cells (LMCs) and their electrical coupling through Cxs, Cx-related lymphedema is proposed to result from dyssynchronous contractions of lymphatic vessels.
objectiveTo determine which Cx isoforms in LMCs and lymphatic endothelial cells are required for the entrainment of lymphatic contraction waves and efficient lymph transport. METHODS AND
resultsWe developed novel methods to quantify the spatiotemporal entrainment of lymphatic contraction waves and used optogenetic techniques to analyze calcium signaling within and between the LMC and the lymphatic endothelial cell layers. Genetic deletion of the major lymphatic endothelial cell Cxs (Cx43, Cx47, or Cx37) revealed that none were necessary for the synchronization of the global calcium events that triggered propagating contraction waves. We identified Cx45 in human and mouse LMCs as the critical Cx mediating the conduction of pacemaking signals and entrained contractions. Smooth muscle-specific Cx45 deficiency resulted in 10- to 18-fold reduction in conduction speed, partial-to-severe loss of contractile coordination, and impaired lymph pump function ex vivo and in vivo. Cx45 deficiency resulted in profound inhibition of lymph transport in vivo, but only under an imposed gravitational load.
conclusionsOur results (1) identify Cx45 as the Cx isoform mediating the entrainment of the contraction waves in LMCs; (2) show that major endothelial Cxs are dispensable for the entrainment of contractions; (3) reveal a lack of coupling between lymphatic endothelial cells and LMCs, in contrast to arterioles; (4) point to lymphatic valve defects, rather than contraction dyssynchrony, as the mechanism underlying GJC2- or GJA1-related lymphedema; and (5) show that a gravitational load exacerbates lymphatic contractile defects in the intact mouse hindlimb, which is likely critical for the development of lymphedema in the adult mouse.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.