Lymphoedema conditions disrupt endothelial barrier function in vitro

Area of Science:

• Cardiovascular Biology
• Lymphatic Physiology
• Endothelial Cell Biology

Background:

• Normal lymphatic vessels exhibit pulsatile contractions driving lymph flow.
• Lymphoedema is associated with impaired lymphatic function and altered flow dynamics.
• The precise impact of lymphoedema on the lymphatic endothelium remains incompletely understood.

Purpose of the Study:

• To investigate the lymphatic flow field in a mouse model of lymphoedema.
• To determine the effects of lymphoedema-associated flow changes on lymphatic endothelial cells (LECs).
• To elucidate the molecular mechanisms underlying flow-induced LEC alterations.

Main Methods:

• Characterization of lymphatic vessel contractility and flow in a CLEC2-deficient lymphoedema mouse model.
• In vitro studies exposing human dermal LECs to simulated lymphoedema (quasi-steady) and normal (pulsatile) flow conditions.
• Assessment of intercellular gap formation, permeability, and molecular signaling pathways (MLC phosphorylation).

Main Results:

• Lymphoedema-associated collecting vessels showed distension, reduced contractility, and a shift from pulsatile to quasi-steady flow.
• Quasi-steady flow, compared to pulsatile flow, increased intercellular gap formation and permeability in LECs.
• Absence of pulsatility (steady pressure or flow) led to increased LEC contraction via MLC phosphorylation, unlike pulsatile conditions.

Conclusions:

• Loss of pulsatility in lymphatic flow, a hallmark of lymphoedema, induces LEC contraction.
• This mechanotransduction process, mediated by MLC phosphorylation, increases intercellular gaps and vascular permeability.
• Altered lymphatic flow dynamics in lymphoedema contribute to endothelial dysfunction and disease progression.