Lymphatic Collecting Vessel: New Perspectives on Mechanisms of Contractile Regulation and Potential Lymphatic Contractile Pathways to Target in Obesity and Metabolic Diseases

Abstract

Obesity and metabolic syndrome pose a significant risk for developing cardiovascular disease and remain a critical healthcare challenge. Given the lymphatic system’s role as a nexus for lipid absorption, immune cell trafficking, interstitial fluid and macromolecule homeostasis maintenance, the impact of obesity and metabolic disease on lymphatic function is a burgeoning field in lymphatic research. Work over the past decade has progressed from the association of an obese phenotype with Prox1 haploinsufficiency and the identification of obesity as a risk factor for lymphedema to consistent findings of lymphatic collecting vessel dysfunction across multiple metabolic disease models and organisms and characterization of obesity-induced lymphedema in the morbidly obese. Critically, recent findings have suggested that restoration of lymphatic function can also ameliorate obesity and insulin resistance, positing lymphatic targeted therapies as relevant pharmacological interventions. There remain, however, significant gaps in our understanding of lymphatic collecting vessel function, particularly the mechanisms that regulate the spontaneous contractile activity required for active lymph propulsion and lymph return in humans. In this article, we will review the current findings on lymphatic architecture and collecting vessel function, including recent advances in the ionic basis of lymphatic muscle contractile activity. We will then discuss lymphatic dysfunction observed with metabolic disruption and potential pathways to target with pharmacological approaches to improve lymphatic collecting vessel function.

Lymphatic muscle cells are unique cells that undergo aging induced changes

“…A KCNK3 single-nucleotide polymorphism (SNP) was associated with development of secondary lymphedema following breast cancer surgery (Smoot et al, 2017), but neither Kcnk3 nor any other two-pore domain potassium channels have yet been demonstrated in LMCs (Lee et al, 2022). Our data show Kcnk3 expression (protein K2P3, also called TASK) in LMCs ( Figure 3F ).…”

“…Dysfunction of the lymphatic system is attributed as the cause of lymphedema and lymphatic diseases, which affect an estimated 7 million patients in the US and 250 million patients worldwide (Rockson, 2018(Rockson, , 2021. Further, there are strong associations for the involvement of the lymphatic system in the pathogenesis of many diseases, including bacterial and filarial infections (Jones et al, 2018;Zhou et al, 2019), inflammatory bowel disease (Rehal et al, 2018), metabolic syndrome (Jiang et al, 2019;Lee et al, 2022;Norden and Kume, 2020), congestive heart failure (Itkin et al, 2021), hypertension (Chachaj et al, 2018), diabetes (Cao et al, 2021) and neurodegenerative diseases (Louveau et al, 2018), including Alzheimer's disease (Da Mesquita et al, 2018). Further, the recovery from many pathologies, including myocardial infarction (Klaourakis et al, 2021;Liu et al, 2020) and bone regeneration (Biswas et al, 2023), also requires the lymphatic system.…”

Intestinal Lymphatic Dysfunction in Kidney Disease

“…[30][31][32] Similarly, symporters play a role in regulating tone and contractility as inhibition of the NKCC (Na + -K + -2CI − cotransporter) cotransporter with furosemide or bumetanide caused LSMC hyperpolarization, vasorelaxation, and a decrease in contraction frequency. 33,34 The rhythmic nature of lymphatic contractions suggests a pacemaking property. Small transient depolarizations (STDs) are thought to set the timing of lymphatic contractions, although the exact nature of the lymphatic pacemaker is still unresolved.…”

“…30–32 Similarly, symporters play a role in regulating tone and contractility as inhibition of the NKCC (Na + -K + -2CI − cotransporter) cotransporter with furosemide or bumetanide caused LSMC hyperpolarization, vasorelaxation, and a decrease in contraction frequency. 33,34…”

A dual-clock-driven model emulating the effects of either Ano1 or IP3R knock-out on lymphatic muscle cell pace-making

“…However, there is incomplete understanding of the mechanisms involved in the oscillatory excitation for intrinsic pumping, restricting the development of pharmacological treatments (Lee et al 2022). Due to the complexity of these pace-making systems, modelling is critical to uncovering the function and failure of the underlying oscillatory mechanisms.…”