Sex Hormones in Lymphedema

Morfoisse, Florent; Zamora, Audrey; Marchaud, Emmanuelle; Nougue, Manon; Diallo, Leila; David, Florian; Roussel, Émilie; Lacazette, Éric; Prats, Anne-Catherine; Tatin, Florence; Garmy‐Susini, Barbara

doi:10.3390/cancers13030530

Cited by 17 publications

(10 citation statements)

References 91 publications

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“…Additionally, the companion modeling paper is based on genetic knockout data, which are currently limited to male mice due to the Y-chromosome-linked transgene. This is of particular importance given that the majority of lymphedema patients, not caused by filarial nematodes, are female, and that female hormones may alter lymphatic contractile function ( Morfoisse et al, 2021 ). However, we suspect that IP3R1 plays a foundational role in regulating lymphatic contractile and pacemaking function.…”

Section: Discussionmentioning

confidence: 99%

IP3R1 underlies diastolic ANO1 activation and pressure-dependent chronotropy in lymphatic collecting vessels

Zawieja,

Pea,

Broyhill

et al. 2023

Journal of General Physiology

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Pressure-dependent chronotropy of murine lymphatic collecting vessels relies on the activation of the Ca2+-activated chloride channel encoded by Anoctamin 1 (Ano1) in lymphatic muscle cells. Genetic ablation or pharmacological inhibition of ANO1 results in a significant reduction in basal contraction frequency and essentially complete loss of pressure-dependent frequency modulation by decreasing the rate of the diastolic depolarization phase of the ionic pacemaker in lymphatic muscle cells (LMCs). Oscillating Ca2+ release from sarcoendoplasmic reticulum Ca2+ channels has been hypothesized to drive ANO1 activity during diastole, but the source of Ca2+ for ANO1 activation in smooth muscle remains unclear. Here, we investigated the role of the inositol triphosphate receptor 1 (Itpr1; Ip3r1) in this process using pressure myography, Ca2+ imaging, and membrane potential recordings in LMCs of ex vivo pressurized inguinal-axillary lymphatic vessels from control or Myh11CreERT2;Ip3r1fl/fl (Ip3r1ismKO) mice. Ip3r1ismKO vessels had significant reductions in contraction frequency and tone but an increased contraction amplitude. Membrane potential recordings from LMCs of Ip3r1ismKO vessels revealed a depressed diastolic depolarization rate and an elongation of the plateau phase of the action potential (AP). Ca2+ imaging of LMCs using the genetically encoded Ca2+ sensor GCaMP6f demonstrated an elongation of the Ca2+ flash associated with an AP-driven contraction. Critically, diastolic subcellular Ca2+ transients were absent in LMCs of Ip3r1ismKO mice, demonstrating the necessity of IP3R1 activity in controlling ANO1-mediated diastolic depolarization. These findings indicate a critical role for IP3R1 in lymphatic vessel pressure-dependent chronotropy and contractile regulation.

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Section: Discussionmentioning

confidence: 99%

IP3R1 underlies diastolic ANO1 activation and pressure-dependent chronotropy in lymphatic collecting vessels

Zawieja,

Pea,

Broyhill

et al. 2023

Journal of General Physiology

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“…Estradiol is proposed to influence the expression of VEGF-C, a growth factor implicated in lymphatic endothelial repair with a known role in lymphedema. The full extent of this relationship, and the role of sex in the development of primary lymphedema, remains to be fully elucidated and may represent an exciting area for therapeutic intervention [ 7 ].…”

Section: Incidence and Classificationmentioning

confidence: 99%

Current Concepts in the Management of Primary Lymphedema

2023

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Primary lymphedema is a heterogeneous group of conditions encompassing all lymphatic anomalies that result in lymphatic swelling. Primary lymphedema can be difficult to diagnose, and diagnosis is often delayed. As opposed to secondary lymphedema, primary lymphedema has an unpredictable disease course, often progressing more slowly. Primary lymphedema can be associated with various genetic syndromes or can be idiopathic. Diagnosis is often clinical, although imaging can be a helpful adjunct. The literature on treating primary lymphedema is limited, and treatment algorithms are largely based on practice patterns for secondary lymphedema. The mainstay of treatment focuses on complete decongestive therapy, including manual lymphatic drainage and compression therapy. For those who fail conservative treatment, surgical treatment can be an option. Microsurgical techniques have shown promise in primary lymphedema, with both lymphovenous bypass and vascularized lymph node transfers demonstrating improved clinical outcomes in a few studies.

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“…Primary lymphedema is a well-recognized sex-linked disease, with a prevalence that is approximately three times higher in females than in males (Morfoisse et al, 2018(Morfoisse et al, , 2021Smeltzer et al, 1985;Vignes et al, 2021). However, the impact of biological sex on LMC in lymphedema is still poorly understood.…”

Section: Lmc Transcription As a Function Of Biological Sexmentioning

confidence: 99%

Lymphatic muscle cells are unique cells that undergo aging induced changes

Lei,

Ruscic,

Roh

et al. 2023

Preprint

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Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas—including LMCs—of collecting lymphatic vessels in mouse dermis at various ages. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and uncovered a pro-inflammatory microenvironment that suppresses the contractile apparatus in advanced-aged LMCs. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to preserve lymphatic vessel function as well as supporting studies to identify genetic causes of primary lymphedema currently with unknown molecular explanation.

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Sex Hormones in Lymphedema

Cited by 17 publications

References 91 publications

IP3R1 underlies diastolic ANO1 activation and pressure-dependent chronotropy in lymphatic collecting vessels

IP3R1 underlies diastolic ANO1 activation and pressure-dependent chronotropy in lymphatic collecting vessels

Current Concepts in the Management of Primary Lymphedema

Lymphatic muscle cells are unique cells that undergo aging induced changes

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