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Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep.

ABSTRACT: Contractile activity in the lymphatic vasculature is essential for maintaining fluid balance within organs and tissues. However, the mechanisms by which collecting lymphatics adapt to changes in fluid load and how these adaptations influence lymphatic contractile activity are unknown. Here we report a model of lymphatic injury based on the ligation of one of two parallel lymphatic vessels in the hind limb of sheep and the evaluation of structural and functional changes in the intact, remodelling lymphatic vessel over a 42-day period. We show that the remodelled lymphatic vessel displayed increasing intrinsic contractile frequency, force generation and vessel compliance, as well as decreasing flow-mediated contractile inhibition via the enzyme endothelial nitric oxide synthase. A computational model of a chain of lymphatic contractile segments incorporating these adaptations predicted increases in the flow-generation capacity of the remodelled vessel at the expense of normal mitochondrial function and elevated oxidative stress within the lymphatic muscle. Our findings may inform interventions for mitigating lymphatic muscle fatigue in patients with dysfunctional lymphatics.

SUBMITTER: Nelson TS

PROVIDER: S-EPMC7549051 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep.

Nelson Tyler S TS Nepiyushchikh Zhanna Z Hooks Joshua S T JST Razavi Mohammad S MS Lewis Tristan T Clement Cristina C CC Thoresen Merrilee M Cribb Matthew T MT Ross Mindy K MK Gleason Rudolph L RL Santambrogio Laura L Peroni John F JF Dixon J Brandon JB

Nature biomedical engineering 20191223 6

Contractile activity in the lymphatic vasculature is essential for maintaining fluid balance within organs and tissues. However, the mechanisms by which collecting lymphatics adapt to changes in fluid load and how these adaptations influence lymphatic contractile activity are unknown. Here we report a model of lymphatic injury based on the ligation of one of two parallel lymphatic vessels in the hind limb of sheep and the evaluation of structural and functional changes in the intact, remodelling ...[more]

PMID: 31873209

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Project description:AimsCardiac remodelling in the ischaemic heart determines prognosis in patients with ischaemic heart disease (IHD), while enhancement of angiogenesis and cell survival has shown great potential for IHD despite translational challenges. Phosphoinositide 3-kinase (PI3K)/Akt signalling pathways play a critical role in promoting angiogenesis and cell survival. However, the effect of PI3Kβ in the ischaemic heart is poorly understood. This study investigates the role of endothelial and cardiomyocyte (CM) PI3Kβ in post-infarct cardiac remodelling.Methods and resultsPI3Kβ catalytic subunit-p110β level was increased in infarcted murine and human hearts. Using cell type-specific loss-of-function approaches, we reported novel and distinct actions of p110β in endothelial cells (ECs) vs. CMs in response to myocardial ischaemic injury. Inactivation of endothelial p110β resulted in marked resistance to infarction and adverse cardiac remodelling with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured ECs with p110β knockout or inhibition displayed preferential PI3Kα/Akt/endothelial nitric oxide synthase signalling that consequently promoted protective signalling and angiogenesis. In contrast, mice with CM p110β-deficiency exhibited adverse post-infarct ventricular remodelling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of CMs to ischaemia-mediated cell death. Disruption of CM p110β signalling compromised nuclear p110β and phospho-Akt levels leading to perturbed gene expression and elevated pro-cell death protein levels, increasing the susceptibility to CM death. A similar divergent response of PI3Kβ endothelial and CM mutant mice was seen using a model of myocardial ischaemia-reperfusion injury.ConclusionThese data demonstrate novel, differential, and cell-specific functions of PI3Kβ in the ischaemic heart. While the loss of endothelial PI3Kβ activity produces cardioprotective effects, CM PI3Kβ is protective against myocardial ischaemic injury.

Dataset Information

Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep.

Publications

Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep.

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